rs762573767

Variant names:

• chr1-1436947-C-T
• rs762573767
• NM_022834.5:c.94C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-1436947-C-T
• chr1-1436947-C-A
• chr1-1436947-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_022834.5(VWA1):​c.94C>T​(p.Arg32*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000156 in 1,607,494 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: VWA1 NM_022834.5 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 1.30
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neuronopathy, distal hereditary motor, autosomal recessive 7

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• neuronopathy, distal hereditary motor, autosomal recessive 5

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 15 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-1436947-C-T is Pathogenic according to our data. Variant chr1-1436947-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 830326.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.94C>T	p.Arg32*	stop_gained	Exon 2 of 3	NP_073745.2
	VWA1	NM_199121.3		c.74-375C>T		intron	N/A	NP_954572.2	Q6PCB0-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWA1	ENST00000476993.2	TSL:1 MANE Select	c.94C>T	p.Arg32*	stop_gained	Exon 2 of 3	ENSP00000417185.1	Q6PCB0-1
	VWA1	ENST00000495558.1	TSL:2	c.-12C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 2	ENSP00000463643.1	J3QLP3
	VWA1	ENST00000895635.1		c.85C>T	p.Arg29*	stop_gained	Exon 2 of 3	ENSP00000565694.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000409 AC: 10 AN: 244670 AF XY: 0.0000451

Gnomad AFR exome AF: 0.000189

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000275

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 24 AN: 1455278 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 723194

African (AFR) AF: 0.0000599 AC: 2 AN: 33382

American (AMR) AF: 0.0000226 AC: 1 AN: 44250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25936

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.0000466 AC: 4 AN: 85806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51990

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1108528

Other (OTH) AF: 0.0000333 AC: 2 AN: 60060

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000577 AC: 7

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Neuromuscular disease (1)
1	-	-	Neuronopathy, distal hereditary motor, autosomal recessive 7 (1)
1	-	-	VWA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	0.072
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.10	N
PhyloP100		1.3
Vest4		0.035
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=53/147	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs762573767; hg19: chr1-1372327; COSMIC: COSV100100548; COSMIC: COSV100100548;