rs756502116

Variant names:

• chr1-1436986-G-A
• rs756502116
• NM_022834.5:c.133G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022834.5(VWA1):​c.133G>A​(p.Val45Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,612,520 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: VWA1 NM_022834.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.69
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.133G>A	p.Val45Ile	missense	Exon 2 of 3	NP_073745.2
	VWA1	NM_199121.3		c.74-336G>A		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.133G>A	p.Val45Ile	missense	Exon 2 of 3	ENSP00000417185.1	Q6PCB0-1
	VWA1	ENST00000895635.1		c.124G>A	p.Val42Ile	missense	Exon 2 of 3	ENSP00000565694.1
	VWA1	ENST00000495558.1	TSL:2	c.28G>A	p.Val10Ile	missense	Exon 2 of 2	ENSP00000463643.1	J3QLP3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000808 AC: 2 AN: 247430 AF XY: 0.0000149

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: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460290 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726408

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111864

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.1	L
PhyloP100		6.7
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.060	N
REVEL	Uncertain	0.41
Sift	Benign	0.98	T
Sift4G	Benign	0.31	T
Polyphen		0.99	D
Vest4		0.40
MVP		0.75
MPC		0.22
ClinPred		0.88	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.072
gMVP		0.47
Mutation Taster		=95/5	polymorphism

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: rs756502116; hg19: chr1-1372366;