Genetic Variant VWA7:p.Ser843Pro (chr6-31765743-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_025258.3(VWA7):c.2527T>C(p.Ser843Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,439,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

VWA7
NM_025258.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.33

Publications

0 publications found

Variant links:

Genes affected

VWA7 (HGNC:13939): (von Willebrand factor A domain containing 7) Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

VWA7 links:

SAPCD1-AS1 (HGNC:39824): (SAPCD1 antisense RNA 1)

SAPCD1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04308474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWA7	NM_025258.3 link	c.2527T>C	p.Ser843Pro	missense_variant	Exon 17 of 17	ENST00000375688.5	NP_079534.2	Q9Y334-1A0A1U9X8T7
SAPCD1-AS1	NR_126423.1 link	n.-155T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWA7	ENST00000375688.5 link	c.2527T>C	p.Ser843Pro	missense_variant	Exon 17 of 17	5	NM_025258.3	ENSP00000364840.4		Q9Y334-1
SAPCD1-AS1	ENST00000419679.1 link	n.-155T>C		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000457

AC:

AN:

218640

AF XY:

0.00

show subpopulations

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:

0.00000139

AC:

AN:

1439170

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714078

show subpopulations

African (AFR)

AF:

0.0000303

AC:

AN:

33046

American (AMR)

AF:

0.00

AC:

AN:

41650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24682

East Asian (EAS)

AF:

0.00

AC:

AN:

39404

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100734

Other (OTH)

AF:

0.00

AC:

AN:

59386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 07, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2527T>C (p.S843P) alteration is located in exon 17 (coding exon 16) of the VWA7 gene. This alteration results from a T to C substitution at nucleotide position 2527, causing the serine (S) at amino acid position 843 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.068

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.0019

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.031

M_CAP

Benign

0.0021

MetaRNN

Benign

0.043

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

-1.3

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.92

REVEL

Benign

0.051

Sift

Benign

0.11

Sift4G

Benign

0.11

Polyphen

0.0

Vest4

0.10

MutPred

0.072

Loss of glycosylation at S843 (P = 0.0222);

MVP

0.030

MPC

0.37

ClinPred

0.072

GERP RS

-9.7

Varity_R

0.056

gMVP

0.23

Mutation Taster

=95/5

polymorphism

(source)

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

Publications

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6-31765743-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over