NM_022834.5:c.208G>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The NM_022834.5(VWA1):c.208G>T(p.Ala70Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000301 in 1,610,358 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A70D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

VWA1
NM_022834.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.02

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008526266).

BP6

Variant 1-1437061-G-T is Benign according to our data. Variant chr1-1437061-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 722916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00148 (225/152356) while in subpopulation AFR AF= 0.0051 (212/41590). AF 95% confidence interval is 0.00454. There are 1 homozygotes in gnomad4. There are 102 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWA1	NM_022834.5 link	c.208G>T	p.Ala70Ser	missense_variant	Exon 2 of 3	ENST00000476993.2	NP_073745.2	Q6PCB0-1
VWA1	NM_199121.3 link	c.74-261G>T		intron_variant	Intron 1 of 2		NP_954572.2	Q6PCB0-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VWA1	ENST00000476993.2 link	c.208G>T	p.Ala70Ser	missense_variant	Exon 2 of 3	1	NM_022834.5	ENSP00000417185.1	Q6PCB0-1
VWA1	ENST00000495558.1 link	c.103G>T	p.Ala35Ser	missense_variant	Exon 2 of 2	2		ENSP00000463643.1	J3QLP3
VWA1	ENST00000471398.1 link	c.328G>T	p.Ala110Ser	missense_variant	Exon 2 of 2	3		ENSP00000464343.1	J3QRR0
VWA1	ENST00000338660.5 link	c.74-261G>T		intron_variant	Intron 1 of 2	2		ENSP00000423404.1	Q6PCB0-3

Frequencies

GnomAD3 genomes

AF:

0.00148

AC:

225

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00511

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

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:

0.00144

GnomAD3 exomes

AF:

0.000378

AC:

AN:

246004

Hom.:

AF XY:

0.000194

AC XY:

AN XY:

133682

show subpopulations

Gnomad AFR exome

AF:

0.00513

Gnomad AMR exome

AF:

0.000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000908

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000178

AC:

259

AN:

1458002

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

100

AN XY:

725016

show subpopulations

Gnomad4 AFR exome

AF:

0.00655

Gnomad4 AMR exome

AF:

0.000383

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000349

GnomAD4 genome

AF:

0.00148

AC:

225

AN:

152356

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

102

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00510

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000542

Hom.:

Bravo

AF:

0.00178

ESP6500AA

AF:

0.00523

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000446

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 25, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.11

.;T;.

Eigen

Benign

-0.14

Eigen_PC

Benign

0.011

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.68

T;T;T

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.0085

T;T;T

MetaSVM

Uncertain

0.32

MutationAssessor

Benign

0.77

.;N;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.030

.;N;.

REVEL

Benign

0.26

Sift

Benign

0.47

.;T;.

Sift4G

Benign

0.91

T;T;T

Polyphen

0.27

.;B;.

Vest4

0.18

MVP

0.92

MPC

0.071

ClinPred

0.023

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.090

gMVP

0.37

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over