VCV001174617.14 - ClinVar

NM_004722.4(AP4M1):c.1137+1G>T

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.

(10)

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_004722.4(AP4M1):c.1137+1G>T

Variation ID: 1174617 Accession: VCV001174617.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q22.1 7: 100106515 (GRCh38) [ NCBI UCSC ] 7: 99704138 (GRCh37) [ 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	Jul 7, 2021	Oct 26, 2024	Apr 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004722.4:c.1137+1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001363671.2:c.1158+1G>T		splice donor
NC_000007.14:g.100106515G>T
NC_000007.13:g.99704138G>T
NG_016312.1:g.10009G>T
NG_029454.1:g.18344C>A
NG_029454.2:g.25656C>A

... more HGVS ... less HGVS

Protein change

Other names

p.Ser342ArgfsTer65

Canonical SPDI

NC_000007.14:100106514:G:T

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.

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

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

dbSNP: rs770705832 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.
AP4M1		-	-	GRCh38 GRCh37	407	495

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.
not provided	Pathogenic (4)	criteria provided, single submitter	Mar 20, 2020	RCV001528225.8
Hereditary spastic paraplegia 50	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Apr 23, 2024	RCV001810068.5
Spastic paraplegia	Likely pathogenic (1)	no assertion criteria provided	Oct 1, 2020	RCV001849519.3
AP4M1-related disorder	Pathogenic (1)	criteria provided, single submitter	Oct 18, 2022	RCV003399328.4

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 (Mar 20, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001818204.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Comment: Published functional studies demonstrate that expression is reduced in heterozygotes and abolished in homozygotes (Verkerk et al., 2009); Canonical splice site variant in a gene … (more) Published functional studies demonstrate that expression is reduced in heterozygotes and abolished in homozygotes (Verkerk et al., 2009); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19559397, 25525159, 29997391, 28492530, 26029708, 32979048, 29096665) (less)
Likely pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 50 Affected status: yes Allele origin: germline	3billion Accession: SCV002058144.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Comment: The variant has been reported to be associated with AP4M1 related disorder (ClinVar ID: VCV001174617, 3billion dataset). It is observed at an extremely low frequency … (more) The variant has been reported to be associated with AP4M1 related disorder (ClinVar ID: VCV001174617, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000012, PM2_M). Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10% (PVS1_S). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: CNS hypomyelination (present) , Cerebral atrophy (present) , Intellectual disability (present) , Microcephaly (present) , Mild short stature (present)
Pathogenic (Apr 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 50 Affected status: yes Allele origin: inherited	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine Accession: SCV002102938.1 First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022	Sex: female
Pathogenic (Apr 06, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 50 Affected status: yes Allele origin: germline	Dr. med. U. Finckh, Human Genetics, Eurofins MVZ Accession: SCV004037214.1 First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 Comment: Homozygous in two siblings with spastic paraplegia. The unaffected parents were both heterozygous carriers.
Pathogenic (Oct 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	AP4M1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004120998.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The AP4M1 c.1137+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in multiple individuals with … (more) The AP4M1 c.1137+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in multiple individuals with cerebral palsy (Verkerk et al 2009. PubMed ID: 19559397; Table 1, Valence et al. 2019. PubMed ID: 29997391; Figure S1, Ebrahimi-Fakhari et al 2020. PubMed ID: 32979048). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-99704138-G-T). Variants that disrupt the consensus splice donor site in AP4M1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Apr 23, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hereditary spastic paraplegia 50 (Autosomal recessive inheritance) Affected status: yes Allele origin: biparental	University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM) Accession: SCV004934094.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Comment: The AP4M1 c.1137+1G>T variant is predicted to disrupt the donor site and interfere with normal splicing. In silico prediction tools, including CADD and MutationTaster, predict … (more) The AP4M1 c.1137+1G>T variant is predicted to disrupt the donor site and interfere with normal splicing. In silico prediction tools, including CADD and MutationTaster, predict this variant to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1174617), it’s classified as pathogenic/Likely Pathogenic. This variant is not reported in the 1000 Genomes Project but is present at a low frequency in the gnomAD database [AF = 1.64e-5]. It is associated with the following publication (PMID: 19559397, 26029708, 29997391). (less) Number of individuals with the variant: 3 Clinical Features: Spastic tetraparesis (present) , Intellectual disability (present) , Cataract (present) , Strabismus (present) , Sensorimotor neuropathy (present) , Corpus callosum, agenesis of (present) , Abnormal … (more) Spastic tetraparesis (present) , Intellectual disability (present) , Cataract (present) , Strabismus (present) , Sensorimotor neuropathy (present) , Corpus callosum, agenesis of (present) , Abnormal facial shape (present) , Microcephaly (present) (less) Age: 8-12 years Sex: mixed Geographic origin: Algeria Comment on evidence: Complete co-segregation between the variant allele and the disease distribution was observed in the patients’ family. The three affected siblings were homozygous for the variant … (more) Complete co-segregation between the variant allele and the disease distribution was observed in the patients’ family. The three affected siblings were homozygous for the variant allele, whereas the unaffected parents were heterozygous carriers. (less) Testing laboratory: WES data were generated at the IGenSeq platform of the ICM Institute (Paris, France)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001808737.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001739600.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001975552.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Likely pathogenic (Oct 01, 2020)	no assertion criteria provided Method: literature only	Spastic paraplegia Affected status: yes Allele origin: germline	Yale Center for Mendelian Genomics, Yale University Study: Yale Center for Mendelian Genomics Accession: SCV002106862.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022	Publications: PubMed (1) PubMed: 32979048

Comment:

Published functional studies demonstrate that expression is reduced in heterozygotes and abolished in homozygotes (Verkerk et al., 2009); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19559397, 25525159, 29997391, 28492530, 26029708, 32979048, 29096665)

Comment:

The variant has been reported to be associated with AP4M1 related disorder (ClinVar ID: VCV001174617, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000012, PM2_M). Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10% (PVS1_S). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The AP4M1 c.1137+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in multiple individuals with cerebral palsy (Verkerk et al 2009. PubMed ID: 19559397; Table 1, Valence et al. 2019. PubMed ID: 29997391; Figure S1, Ebrahimi-Fakhari et al 2020. PubMed ID: 32979048). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-99704138-G-T). Variants that disrupt the consensus splice donor site in AP4M1 are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

The AP4M1 c.1137+1G>T variant is predicted to disrupt the donor site and interfere with normal splicing. In silico prediction tools, including CADD and MutationTaster, predict this variant to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1174617), it’s classified as pathogenic/Likely Pathogenic. This variant is not reported in the 1000 Genomes Project but is present at a low frequency in the gnomAD database [AF = 1.64e-5]. It is associated with the following publication (PMID: 19559397, 26029708, 29997391).

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
Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.	Ebrahimi-Fakhari D	Brain : a journal of neurology	2020	PMID: 32979048

Text-mined citations for rs770705832 ...

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 Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_004722.4(AP4M1):c.1137+1G>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs770705832 ...