Genetic Variant VWA1:p.Gly21AlafsTer12 (chr1-1435798-TGGCGCGGAGC-T) – ACMG Classification: Likely_pathogenic (6 pts)

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

Publications

1 publications found

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:

LINC01770 (HGNC:52560): (long intergenic non-protein coding RNA 1770)

LINC01770 links:

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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 18 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 VariationId is 830324.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022834.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWA1	NM_022834.5	MANE Select	c.62_71delGCGCGGAGCG	p.Gly21AlafsTer12	frameshift splice_region	Exon 1 of 3	NP_073745.2
	VWA1	NM_199121.3		c.62_71delGCGCGGAGCG	p.Gly21AlafsTer291	frameshift splice_region	Exon 1 of 3	NP_954572.2	Q6PCB0-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VWA1	ENST00000476993.2	TSL:1 MANE Select	c.62_71delGCGCGGAGCG	p.Gly21AlafsTer12	frameshift splice_region	Exon 1 of 3	ENSP00000417185.1	Q6PCB0-1
VWA1	ENST00000895635.1		c.62_71delGCGCGGAGCG	p.Gly21AlafsTer9	frameshift splice_region	Exon 1 of 3	ENSP00000565694.1
VWA1	ENST00000895634.1		c.62_71delGCGCGGAGCG	p.Gly21AlafsTer27	frameshift splice_region	Exon 1 of 2	ENSP00000565693.1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000499

AC:

AN:

20022

American (AMR)

AF:

0.00

AC:

AN:

8788

Ashkenazi Jewish (ASJ)

AF:

0.000168

AC:

AN:

11892

East Asian (EAS)

AF:

0.0000715

AC:

AN:

13984

South Asian (SAS)

AF:

0.000258

AC:

AN:

38810

European-Finnish (FIN)

AF:

0.0000549

AC:

AN:

18224

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2840

European-Non Finnish (NFE)

AF:

0.0000311

AC:

AN:

899274

Other (OTH)

AF:

0.0000257

AC:

AN:

38960

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000182810), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.393

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

African (AFR)

AF:

0.0000243

AC:

AN:

41138

American (AMR)

AF:

0.00

AC:

AN:

15042

Ashkenazi Jewish (ASJ)

AF:

0.00117

AC:

AN:

3424

East Asian (EAS)

AF:

0.00

AC:

AN:

5124

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9690

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000299

AC:

AN:

66972

Other (OTH)

AF:

0.00

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neuronopathy, distal hereditary motor, autosomal recessive 7 (2)

Neuromuscular disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.1

Mutation Taster

=42/158

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over