Variant 1-1435798-TGGCGCGGAGC-TGGCGCGGAGCGGCGCGGAGC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_022834.5(VWA1):c.62_71dupGCGCGGAGCG(p.Gly25ArgfsTer74) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000931 in 1,202,546 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00097 ( 1 hom. )

Consequence

VWA1
NM_022834.5 frameshift, splice_region

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 0.706

Variant links:

Genes affected

VWA1 (HGNC:30910): (von Willebrand factor A domain containing 1) VWA1 belongs to the von Willebrand factor (VWF; MIM 613160) A (VWFA) domain superfamily of extracellular matrix proteins and appears to play a role in cartilage structure and function (Fitzgerald et al., 2002 [PubMed 12062410]).[supplied by OMIM, Nov 2010]

VWA1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-1435798-T-TGGCGCGGAGC is Pathogenic according to our data. Variant chr1-1435798-T-TGGCGCGGAGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 830327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWA1	NM_022834.5 link	c.62_71dupGCGCGGAGCG	p.Gly25ArgfsTer74	frameshift_variant, splice_region_variant	Exon 1 of 3	ENST00000476993.2	NP_073745.2	Q6PCB0-1
VWA1	NM_199121.3 link	c.62_71dupGCGCGGAGCG	p.Gly25ArgfsTer53	frameshift_variant, splice_region_variant	Exon 1 of 3		NP_954572.2	Q6PCB0-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VWA1	ENST00000476993.2 link	c.62_71dupGCGCGGAGCG	p.Gly25ArgfsTer74	frameshift_variant, splice_region_variant	Exon 1 of 3	1	NM_022834.5	ENSP00000417185.1	Q6PCB0-1
VWA1	ENST00000471398.1 link	c.62_71dupGCGCGGAGCG	p.Gly25ArgfsTer14	frameshift_variant, splice_region_variant	Exon 1 of 2	3		ENSP00000464343.1	J3QRR0
VWA1	ENST00000338660.5 link	c.62_71dupGCGCGGAGCG	p.Gly25ArgfsTer53	frameshift_variant, splice_region_variant	Exon 1 of 3	2		ENSP00000423404.1	Q6PCB0-3
VWA1	ENST00000495558.1 link	c.-33+664_-33+673dupGCGCGGAGCG		intron_variant	Intron 1 of 1	2		ENSP00000463643.1	J3QLP3

Frequencies

GnomAD3 genomes

AF:

0.000669

AC:

100

AN:

149504

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000510

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000665

Gnomad ASJ

AF:

0.000292

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000956

Gnomad OTH

AF:

0.000971

GnomAD4 exome

AF:

0.000969

AC:

1020

AN:

1052936

Hom.:

Cov.:

AF XY:

0.000991

AC XY:

507

AN XY:

511496

show subpopulations

Gnomad4 AFR exome

AF:

0.000749

Gnomad4 AMR exome

AF:

0.000455

Gnomad4 ASJ exome

AF:

0.0000841

Gnomad4 EAS exome

AF:

0.0000715

Gnomad4 SAS exome

AF:

0.0000772

Gnomad4 FIN exome

AF:

0.0000549

Gnomad4 NFE exome

AF:

0.00106

Gnomad4 OTH exome

AF:

0.00105

GnomAD4 genome

AF:

0.000668

AC:

100

AN:

149610

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

AN XY:

73002

show subpopulations

Gnomad4 AFR

AF:

0.000509

Gnomad4 AMR

AF:

0.000664

Gnomad4 ASJ

AF:

0.000292

Gnomad4 EAS

AF:

0.000196

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000956

Gnomad4 OTH

AF:

0.000961

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronopathy, distal hereditary motor, autosomal recessive 7

Pathogenic:5

Feb 05, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshifting variant in exon 1 of 3 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous or homozygous change in individuals with neuromyopathy (PMID: 33459760) and hereditary motor neuropathy (PMID: 33559681). The c.62_71dup (p.Gly25ArgfsTer74) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0333% (15/45050) and thus is presumed to be rare. Based on the available evidence, the c.62_71dup (p.Gly25ArgfsTer74) variant is classified as Pathogenic. -

Apr 26, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 17, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 22, 2024

Neurogenomics Lab, Neuroscience Institute, University Of Cape Town

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/. -

not provided

Pathogenic:2

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

VWA1: PVS1, PM2, PM3 -

Jan 12, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuromuscular disease

Pathogenic:1

Jan 01, 2020

Section for Clinical Neurogenetics, University of Tübingen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

VWA1-related disorder

Pathogenic:1

Sep 16, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The VWA1 c.62_71dup10 variant is predicted to result in a frameshift and premature protein termination (p.Gly25Argfs*74). This variant has been reported in the compound heterozygous and homozygous state in individuals from mutliple unrelated families with neuromyopathy (Deschauer et al 2021. PubMed ID: 33459760; Pagnamenta AT et al 2021. PubMed ID: 33559681). This variant is reported in 0.070% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-1371178-T-TGGCGCGGAGC). Frameshift variants in VWA1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over