chr1-1437053-G-A

Variant names:

• chr1-1437053-G-A
• rs542170050
• NM_022834.5:c.200G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_022834.5(VWA1):​c.200G>A​(p.Gly67Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000348 in 1,611,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G67S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: VWA1 NM_022834.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.61
• 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_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.40455917).

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.200G>A	p.Gly67Asp	missense	Exon 2 of 3	NP_073745.2
	VWA1	NM_199121.3		c.74-269G>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.200G>A	p.Gly67Asp	missense	Exon 2 of 3	ENSP00000417185.1	Q6PCB0-1
	VWA1	ENST00000895635.1		c.191G>A	p.Gly64Asp	missense	Exon 2 of 3	ENSP00000565694.1
	VWA1	ENST00000495558.1	TSL:2	c.95G>A	p.Gly32Asp	missense	Exon 2 of 2	ENSP00000463643.1	J3QLP3

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152246 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: 0.00192

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: 0.000118 AC: 29 AN: 246550 AF XY: 0.000142

Gnomad AFR exome AF: 0.0000626

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00153

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1458826 Hom.: 0 Cov.: 31 AF XY: 0.0000331 AC XY: 24 AN XY: 725576

African (AFR) AF: 0.0000299 AC: 1 AN: 33462

American (AMR) AF: 0.0000225 AC: 1 AN: 44458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.000680 AC: 27 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111150

Other (OTH) AF: 0.000265 AC: 16 AN: 60290

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74502

African (AFR) AF: 0.0000240 AC: 1 AN: 41592

American (AMR) AF: 0.00 AC: 0 AN: 15314

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

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000826 AC: 10

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

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	0.076
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	22
DANN	Benign	0.82
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.062
Eigen_PC	Benign	-0.0074
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.40	T
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.6
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.62
Sift	Benign	0.038	D
Sift4G	Benign	0.11	T
Polyphen		0.25	B
Vest4		0.42
MutPred		0.72		Gain of solvent accessibility (P = 0.0648)
MVP		0.90
MPC		0.13
ClinPred		0.29	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.46
gMVP		0.90
Mutation Taster		=34/66	disease causing

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: rs542170050; hg19: chr1-1372433;