chr1-1435798-TGGCGCGGAGC-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPP5_Moderate

The NM_022834.5(VWA1):c.62_71delGCGCGGAGCG(p.Gly21AlafsTer12) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000424 in 1,202,298 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

VWA1
NM_022834.5 frameshift, splice_region

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 1.14

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:

LOC107985729 (HGNC:):

LOC107985729 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 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.

PP5

Variant 1-1435798-TGGCGCGGAGC-T is Pathogenic according to our data. Variant chr1-1435798-TGGCGCGGAGC-T is described in ClinVar as [Pathogenic]. Clinvar id is 830324.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-1435798-TGGCGCGGAGC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWA1	NM_022834.5 link	c.62_71delGCGCGGAGCG	p.Gly21AlafsTer12	frameshift_variant, splice_region_variant	Exon 1 of 3	ENST00000476993.2	NP_073745.2	Q6PCB0-1
VWA1	NM_199121.3 link	c.62_71delGCGCGGAGCG	p.Gly21AlafsTer291	frameshift_variant, splice_region_variant	Exon 1 of 3		NP_954572.2	Q6PCB0-3
LOC107985729	XM_017003066.2 link	c.649_658delGGCGCGGAGC		downstream_gene_variant			XP_016858555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VWA1	ENST00000476993.2 link	c.62_71delGCGCGGAGCG	p.Gly21AlafsTer12	frameshift_variant, splice_region_variant	Exon 1 of 3	1	NM_022834.5	ENSP00000417185.1	Q6PCB0-1
VWA1	ENST00000471398.1 link	c.62_71delGCGCGGAGCG	p.Gly21AlafsTer52	frameshift_variant, splice_region_variant	Exon 1 of 2	3		ENSP00000464343.1	J3QRR0
VWA1	ENST00000338660.5 link	c.62_71delGCGCGGAGCG	p.Gly21AlafsTer291	frameshift_variant, splice_region_variant	Exon 1 of 3	2		ENSP00000423404.1	Q6PCB0-3
VWA1	ENST00000495558.1 link	c.-33+664_-33+673delGCGCGGAGCG		intron_variant	Intron 1 of 1	2		ENSP00000463643.1	J3QLP3

Frequencies

GnomAD3 genomes

AF:

0.0000468

AC:

AN:

149504

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00117

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000299

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

16854

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000418

AC:

AN:

1052794

Hom.:

AF XY:

0.0000489

AC XY:

AN XY:

511400

show subpopulations

Gnomad4 AFR exome

AF:

0.0000499

AC:

AN:

20022

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

8788

Gnomad4 ASJ exome

AF:

0.000168

AC:

AN:

11892

Gnomad4 EAS exome

AF:

0.0000715

AC:

AN:

13984

Gnomad4 SAS exome

AF:

0.000258

AC:

AN:

38810

Gnomad4 FIN exome

AF:

0.0000549

AC:

AN:

18224

Gnomad4 NFE exome

AF:

0.0000311

AC:

AN:

899274

Gnomad4 Remaining exome

AF:

0.0000257

AC:

AN:

38960

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000468

AC:

AN:

149504

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

72886

show subpopulations

Gnomad4 AFR

AF:

0.0000243

AC:

0.0000243084

AN:

0.0000243084

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00117

AC:

0.00116822

AN:

0.00116822

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000299

AC:

0.0000298632

AN:

0.0000298632

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000340

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neuronopathy, distal hereditary motor, autosomal recessive 7

Pathogenic:2

Feb 26, 2024

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with VWA1-related disorder (ClinVar ID: VCV000830324 /PMID: 33459760). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Oct 17, 2023

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=42/158

disease causing (ClinVar)

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