VCV000812649.21 - ClinVar

NM_016146.6(TRAPPC4):c.454+3A>G

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(11)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_016146.6(TRAPPC4):c.454+3A>G

Variation ID: 812649 Accession: VCV000812649.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q23.3 11: 118890966 (GRCh37) [ NCBI UCSC ] 11: 119020256 (GRCh38) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 22, 2020	Feb 4, 2024	Dec 16, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_016146.6:c.454+3A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001318486.2:c.136+939A>G		intron variant
NM_001318488.2:c.454+3A>G		intron variant
NM_001318489.2:c.292+3A>G		intron variant
NM_001318490.2:c.325+3A>G		intron variant
NM_001318492.2:c.139+3A>G		intron variant
NM_001318494.2:c.175+1286A>G		intron variant
NC_000011.10:g.119020256A>G
NC_000011.9:g.118890966A>G

... more HGVS ... less HGVS

Protein change

Other names

IVS3DS, A-G, +3

Canonical SPDI

NC_000011.10:119020255:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00020

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023

Trans-Omics for Precision Medicine (TOPMed) 0.00023

The Genome Aggregation Database (gnomAD) 0.00025

Links

OMIM: 610971.0001 dbSNP: rs375776811 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TRAPPC4		-	-	GRCh38 GRCh38 GRCh37	55	95

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy	Pathogenic/Likely pathogenic (9)	criteria provided, multiple submitters, no conflicts	Dec 16, 2022	RCV001003468.20
Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies	Pathogenic (1)	criteria provided, single submitter	Nov 16, 2020	RCV001267711.2
not provided	Pathogenic (1)	criteria provided, single submitter	-	RCV001281626.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Apr 14, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV001432141.1 First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020	Number of individuals with the variant: 1 Clinical Features: Spasticity (present) , Profound global developmental delay (present) , Postnatal microcephaly (present) , Optic disc pallor (present) , Optic atrophy (present) , Obstructive sleep apnea … (more) Spasticity (present) , Profound global developmental delay (present) , Postnatal microcephaly (present) , Optic disc pallor (present) , Optic atrophy (present) , Obstructive sleep apnea syndrome (present) , Infantile spasms (present) , Hypertonia (present) , Hip dysplasia (present) , Generalized myoclonic seizures (present) , Dysphagia (present) , Developmental regression (present) , Cortical visual impairment (present) , Cerebral atrophy (present) , Brisk reflexes (present) (less) Age: 0-9 years Sex: female Ethnicity/Population group: Causasians Tissue: blood
Pathogenic (Nov 16, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001445963.1 First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020	Publications: PubMed (3) PubMed: 32125366‚ 31794024‚ 32901138 Comment: The homozygous c.454+3A>G variant in TRAPPC4 was identified by our study in 1 individual with early-infantile neurodegenerative syndrome. This individual along with at least another … (more) The homozygous c.454+3A>G variant in TRAPPC4 was identified by our study in 1 individual with early-infantile neurodegenerative syndrome. This individual along with at least another 22 affected individuals from 16 families were reported in the literature (PMID: 32901138, 31794024, 32125366). This variant has also been identified in 0.04% (50/128792) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs375776811). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. In addition, this variant has also been reported in ClinVar (Variation ID#: 812649) and has been interpreted as pathogenic by OMIM. Of the at least 23 affected individuals, all were homozygotes, which increases the likelihood that the c.454+3A>G variant is pathogenic (PMID: 32901138, 31794024, 32125366). In vitro functional studies provide some evidence that the variant may impact protein function (PMID: 31794024). However, these types of assays may not accurately represent biological function. RNAseq analysis performed on fibroblast cells from an affected patient shows alternative splicing in 59% of the reads and predicted to lead to skipping of exon 3 (PMID: 32901138). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive early-infantile neurodegenerative syndrome. ACMG/AMP Criteria applied: PS3, PM3, PP1_strong (Richards 2015). (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Laboratoire de Génétique Moléculaire, CHU Bordeaux Accession: SCV001468957.1 First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021
Pathogenic (Feb 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy Affected status: yes Allele origin: germline	DASA Accession: SCV002073779.1 First in ClinVar: Feb 10, 2022 Last updated: Feb 10, 2022	Publications: PubMed (3) PubMed: 32901138‚ 32125366‚ 31794024 Comment: Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 32901138) - PS3_supporting. This sequence change … (more) Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 32901138) - PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 812649 PMID: 32125366; 31794024; 32901138; 31794024) - PS4. The variant is present at low allele frequencies population databases (rs375776811 – gnomAD 0.002563%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The c.454+3A>G was detected in trans with a pathogenic variant (PMID: 32125366; 31794024; 32901138; 31794024) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 32901138; 31794024). - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic. (less) Number of individuals with the variant: 1 Sex: male Geographic origin: Brazil
Pathogenic (Sep 09, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002512575.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Comment: ACMG classification criteria: PS3 supporting, PS4 strong, PM3 moderate, PP1 strong Geographic origin: Brazil
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002519895.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022
Pathogenic (Sep 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002557974.2 First in ClinVar: Aug 08, 2022 Last updated: Dec 24, 2022	Publications: PubMed (1) PubMed: 31794024 Comment: Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease … (more) Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant has been shown to cause nonsense-mediated decay (NMD) and loss of protein (PMID: 31794024). (P) 0210 - Splice site variant (canonical or non-canonical) proven to affect splicing/expression of the transcript with a known effect on protein structure. This variant has been shown to result in exon 3 skipping causing a frameshift (p.(Leu120Aspfs*9; intron 3 of 4; PMID: 31794024). (N) 0252 - Variant is homozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (68 heterozygotes, 0 homozygotes). (P) 0508 - In-silico predictions for abnormal splicing are conflicting. (N) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in multiple unrelated families with early-onset seizures, developmental delay, microcephaly, sensorineural deafness, spastic quadriparesis and progressive cortical and cerebellar atrophy (PMID: 31794024). (P) 0901 - Strong evidence for segregation with disease. The variant was shown to segregate with disease in three independent families (PMID: 31794024). (P) 1001 - Strong functional evidence supporting abnormal protein function. Fibroblasts from an affected homozygous individual showed impaired TRAPP complex assembly and golgi trafficking (PMID: 31794024). (P) 1205 - Variant is maternally inherited. (N) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
Pathogenic (Nov 16, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV003799173.2 First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023	Comment: PM4, PP1, PS3_Very Strong
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy Affected status: yes Allele origin: biparental	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: CSER-HudsonAlpha Accession: SCV004009636.1 First in ClinVar: Jul 08, 2023 Last updated: Jul 08, 2023	Number of individuals with the variant: 1 Clinical Features: Brain atrophy (present) , Intellectual disability, severe (present) , Developmental regression (present) , Delayed speech and language development (present)
Likely pathogenic (Dec 16, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003812198.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Feb 28, 2023)	no assertion criteria provided Method: literature only	NEURODEVELOPMENTAL DISORDER WITH EPILEPSY, SPASTICITY, AND BRAIN ATROPHY Affected status: not provided Allele origin: germline	OMIM Accession: SCV001161770.3 First in ClinVar: Feb 22, 2020 Last updated: Mar 18, 2023	Publications: PubMed (2) PubMed: 32901138‚ 32125366 Van Bergen, N. J. Personal (more...) Van Bergen, N. J. Personal Communication. 2020. Melbourne, Australia Comment on evidence: In 7 children from 3 unrelated families with neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy (NEDESBA; 618741), Van Bergen et al. (2020) identified a … (more) In 7 children from 3 unrelated families with neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy (NEDESBA; 618741), Van Bergen et al. (2020) identified a homozygous A-to-G transition (c.454+3A-G, NM_016146.5) in intron 3 of the TRAPPC4 gene, resulting in a splice site alteration, the skipping of exon 3, a frameshift, and premature termination (Leu120AspfsTer9). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. It was found 68 times in heterozygous state in the gnomAD database (frequency of 0.0002419), but never in homozygosity. Analysis of fibroblasts derived from 1 patient confirmed the splicing defect, with almost complete loss of the wildtype transcript and increased production of an aberrant transcript, suggesting an incompletely penetrant splicing defect. Western blot analysis showed some production of the wildtype protein, but at significantly decreased levels compared to controls; a truncated protein was not detected, consistent with nonsense-mediated mRNA decay of the mutant transcript. Fibroblasts derived from 1 patient showed overall decreased levels of fully-assembled TRAPP complexes compared to controls. Haplotype analysis was not consistent with a founder effect, but rather suggested a mutational hotspot. One additional affected deceased individual did not have DNA tested, but most likely carried the same homozygous mutation. In 23 patients from 17 unrelated families with NEDESBA, Ghosh et al. (2021) identified homozygosity for the c.454+3A-G mutation in exon 3 of the TRAPPC4 gene. The mutation was identified by whole-exome or whole-genome sequencing. The minor allele frequencies of the c.454+3A-G mutation in sequencing databases was high, e.g., 0.024% in gnomAD (v.2.1.1), 0.054% in 1000 Genomes Project, and 0.033% in NHLBI Exome Sequencing Project; however, no shared haplotype was identified in their or previously studies families. RNA sequencing in skin fibroblasts from 1 patient (patient 15) revealed partial exon 3 skipping of TRAPPC4 due to use of a cryptic splice donor site, which was predicted to result in a premature stop and nonsense-mediated decay. In a 1 year and 7-month-old girl with NEDESBA, who was born to parents Indian origin without reported consanguinity, Kaur et al. (2020) identified homozygosity for the c.454+3A-G mutation in exon 3 of the TRAPPC4 gene. The mutation, which was found by exome sequencing, was present in heterozygous state in the parents. (less)
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Comment:

The homozygous c.454+3A>G variant in TRAPPC4 was identified by our study in 1 individual with early-infantile neurodegenerative syndrome. This individual along with at least another 22 affected individuals from 16 families were reported in the literature (PMID: 32901138, 31794024, 32125366). This variant has also been identified in 0.04% (50/128792) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs375776811). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. In addition, this variant has also been reported in ClinVar (Variation ID#: 812649) and has been interpreted as pathogenic by OMIM. Of the at least 23 affected individuals, all were homozygotes, which increases the likelihood that the c.454+3A>G variant is pathogenic (PMID: 32901138, 31794024, 32125366). In vitro functional studies provide some evidence that the variant may impact protein function (PMID: 31794024). However, these types of assays may not accurately represent biological function. RNAseq analysis performed on fibroblast cells from an affected patient shows alternative splicing in 59% of the reads and predicted to lead to skipping of exon 3 (PMID: 32901138). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive early-infantile neurodegenerative syndrome. ACMG/AMP Criteria applied: PS3, PM3, PP1_strong (Richards 2015).

Comment:

Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 32901138) - PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 812649 PMID: 32125366; 31794024; 32901138; 31794024) - PS4. The variant is present at low allele frequencies population databases (rs375776811 – gnomAD 0.002563%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The c.454+3A>G was detected in trans with a pathogenic variant (PMID: 32125366; 31794024; 32901138; 31794024) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 32901138; 31794024). - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic.

Comment:

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant has been shown to cause nonsense-mediated decay (NMD) and loss of protein (PMID: 31794024). (P) 0210 - Splice site variant (canonical or non-canonical) proven to affect splicing/expression of the transcript with a known effect on protein structure. This variant has been shown to result in exon 3 skipping causing a frameshift (p.(Leu120Aspfs*9; intron 3 of 4; PMID: 31794024). (N) 0252 - Variant is homozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (68 heterozygotes, 0 homozygotes). (P) 0508 - In-silico predictions for abnormal splicing are conflicting. (N) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in multiple unrelated families with early-onset seizures, developmental delay, microcephaly, sensorineural deafness, spastic quadriparesis and progressive cortical and cerebellar atrophy (PMID: 31794024). (P) 0901 - Strong evidence for segregation with disease. The variant was shown to segregate with disease in three independent families (PMID: 31794024). (P) 1001 - Strong functional evidence supporting abnormal protein function. Fibroblasts from an affected homozygous individual showed impaired TRAPP complex assembly and golgi trafficking (PMID: 31794024). (P) 1205 - Variant is maternally inherited. (N) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome.	Ghosh SG	European journal of human genetics : EJHG	2021	PMID: 32901138
Recurrent bi-allelic splicing variant c.454+3A>G in TRAPPC4 is associated with progressive encephalopathy and muscle involvement.	Kaur P	Brain : a journal of neurology	2020	PMID: 32125366
Deficiencies in vesicular transport mediated by TRAPPC4 are associated with severe syndromic intellectual disability.	Van Bergen NJ	Brain : a journal of neurology	2020	PMID: 31794024
Van Bergen, N. J. Personal Communication. 2020. Melbourne, Australia	-	-	-	-

Text-mined citations for rs375776811 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jun 23, 2024

ClinVar Genomic variation as it relates to human health

NM_016146.6(TRAPPC4):c.454+3A>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs375776811 ...