VCV000265274.15 - ClinVar

NM_012470.4(TNPO3):c.2542del (p.Tyr848fs)

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.

(5)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(4)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_012470.4(TNPO3):c.2542del (p.Tyr848fs)

Variation ID: 265274 Accession: VCV000265274.15

Type and length

Deletion, 1 bp

Location

Cytogenetic: 7q32.1 7: 128970204 (GRCh38) [ NCBI UCSC ] 7: 128610258 (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	Oct 10, 2016	Feb 28, 2024	Jan 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_012470.4:c.2542del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_036602.1:p.Tyr848fs	frameshift
NM_001191028.3:c.2350del	NP_001177957.2:p.Tyr784fs	frameshift
NM_001382216.1:c.2644del	NP_001369145.1:p.Tyr882fs	frameshift
NM_001382217.1:c.2623del	NP_001369146.1:p.Tyr875fs	frameshift
NM_001382218.1:c.2542del	NP_001369147.1:p.Tyr848fs	frameshift
NM_001382219.1:c.2434del	NP_001369148.1:p.Tyr812fs	frameshift
NM_001382220.1:c.2401del	NP_001369149.1:p.Tyr801fs	frameshift
NM_001382221.1:c.2398del	NP_001369150.1:p.Tyr800fs	frameshift
NM_001382222.1:c.2395del	NP_001369151.1:p.Tyr799fs	frameshift
NM_001382223.1:c.2350del	NP_001369152.1:p.Tyr784fs	frameshift
NM_012470.3:c.2542delT
NR_034053.3:n.3044del		non-coding transcript variant
NR_167911.1:n.3131del		non-coding transcript variant
NR_167912.1:n.2989del		non-coding transcript variant
NR_167913.1:n.2791del		non-coding transcript variant
NR_167914.1:n.2951del		non-coding transcript variant
NR_167915.1:n.3207del		non-coding transcript variant
NR_167916.1:n.2681del		non-coding transcript variant
NR_167917.1:n.2714del		non-coding transcript variant
NR_167918.1:n.3169del		non-coding transcript variant
NR_167919.1:n.3008del		non-coding transcript variant
NR_167920.1:n.2967del		non-coding transcript variant
NR_167921.1:n.3169del		non-coding transcript variant
NR_167922.1:n.3005del		non-coding transcript variant
NR_167923.1:n.2806del		non-coding transcript variant
NR_167924.1:n.2883del		non-coding transcript variant
NR_167925.1:n.2806del		non-coding transcript variant
NR_167926.1:n.2817del		non-coding transcript variant
NR_167927.1:n.3110del		non-coding transcript variant
NC_000007.14:g.128970204del
NC_000007.13:g.128610258del
NG_023428.1:g.89970del

... more HGVS ... less HGVS

Protein change

Y784fs, Y848fs, Y799fs, Y800fs, Y801fs, Y812fs, Y875fs, Y882fs

Other names

Canonical SPDI

NC_000007.14:128970203:A:

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.

The Genome Aggregation Database (gnomAD) 0.00002

Exome Aggregation Consortium (ExAC) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00004

Links

ClinGen: CA4477852 dbSNP: rs773574448 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.
TNPO3		-	-	GRCh38 GRCh37	615	674

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	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	May 14, 2023	RCV000255285.8
Autosomal dominant limb-girdle muscular dystrophy type 1F	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 8, 2024	RCV000794144.6
not specified	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2019	RCV000791172.3

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.
Likely pathogenic (May 14, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321972.8 First in ClinVar: Oct 10, 2016 Last updated: May 27, 2023	Comment: Identified in an individual with a developmental disorder who also had variants in several other genes associated with neurodevelopmental disorders (Deciphering Developmental Disorders Study, 2017); … (more) Identified in an individual with a developmental disorder who also had variants in several other genes associated with neurodevelopmental disorders (Deciphering Developmental Disorders Study, 2017); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 31674007, 31785789, 28135719) (less)
Uncertain significance (Jun 01, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000708692.2 First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TNPO3 Number of individuals with the variant: 1 Sex: mixed
Uncertain significance (Apr 27, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: yes Allele origin: unknown	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000930448.1 First in ClinVar: Aug 04, 2019 Last updated: Aug 04, 2019	Geographic origin: Iran
Uncertain significance (May 29, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal dominant limb-girdle muscular dystrophy type 1F Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002059634.1 First in ClinVar: Jan 14, 2022 Last updated: Jan 14, 2022
Uncertain significance (Jan 08, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Autosomal dominant limb-girdle muscular dystrophy type 1F Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000933534.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 31674007 Comment: This sequence change creates a premature translational stop signal (p.Tyr848Ilefs25) in the TNPO3 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Tyr848Ilefs25) in the TNPO3 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TNPO3 cause disease. This variant is present in population databases (rs773574448, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with TNPO3-related conditions (PMID: 31674007). ClinVar contains an entry for this variant (Variation ID: 265274). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)

Comment:

Identified in an individual with a developmental disorder who also had variants in several other genes associated with neurodevelopmental disorders (Deciphering Developmental Disorders Study, 2017); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 31674007, 31785789, 28135719)

Comment:

This sequence change creates a premature translational stop signal (p.Tyr848Ilefs*25) in the TNPO3 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TNPO3 cause disease. This variant is present in population databases (rs773574448, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with TNPO3-related conditions (PMID: 31674007). ClinVar contains an entry for this variant (Variation ID: 265274). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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
Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort.	Wu H	Clinical genetics	2020	PMID: 31674007
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TNPO3	-	-	-	-

Text-mined citations for rs773574448 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_012470.4(TNPO3):c.2542del (p.Tyr848fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs773574448 ...