Variant 7-12356133-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001135924.3(VWDE):c.3723T>G(p.Cys1241Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000697 in 1,551,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00070 ( 0 hom. )

Consequence

VWDE
NM_001135924.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.21

Variant links:

Genes affected

VWDE (HGNC:21897): (von Willebrand factor D and EGF domains) Predicted to enable signaling receptor binding activity. Predicted to be involved in anatomical structure development. Predicted to be active in cell surface and extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

VWDE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.878

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VWDE	NM_001135924.3 linkuse as main transcript	c.3723T>G	p.Cys1241Trp	missense_variant	18/29	ENST00000275358.8	NP_001129396.1
VWDE	NM_001346972.2 linkuse as main transcript	c.3378T>G	p.Cys1126Trp	missense_variant	16/27		NP_001333901.1
VWDE	NM_001346973.2 linkuse as main transcript	c.2913T>G	p.Cys971Trp	missense_variant	16/27		NP_001333902.1
VWDE	NR_144534.2 linkuse as main transcript	n.3872T>G		non_coding_transcript_exon_variant	18/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWDE	ENST00000275358.8 linkuse as main transcript	c.3723T>G	p.Cys1241Trp	missense_variant	18/29	5	NM_001135924.3	ENSP00000275358	P1	Q8N2E2-1
VWDE	ENST00000452576.6 linkuse as main transcript	c.3723T>G	p.Cys1241Trp	missense_variant, NMD_transcript_variant	18/30	1		ENSP00000401687
VWDE	ENST00000644150.1 linkuse as main transcript	c.198T>G	p.Cys66Trp	missense_variant	1/3			ENSP00000495749
VWDE	ENST00000521169.5 linkuse as main transcript	c.*2101T>G		3_prime_UTR_variant, NMD_transcript_variant	15/26	5		ENSP00000428810

Frequencies

GnomAD3 genomes

AF:

0.000644

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

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:

0.00112

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000474

AC:

AN:

156204

Hom.:

AF XY:

0.000495

AC XY:

AN XY:

82838

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000608

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:

0.000960

Gnomad OTH exome

AF:

0.000228

GnomAD4 exome

AF:

0.000703

AC:

984

AN:

1399146

Hom.:

Cov.:

AF XY:

0.000665

AC XY:

459

AN XY:

690096

show subpopulations

Gnomad4 AFR exome

AF:

0.0000317

Gnomad4 AMR exome

AF:

0.000504

Gnomad4 ASJ exome

AF:

0.0000397

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000203

Gnomad4 NFE exome

AF:

0.000864

Gnomad4 OTH exome

AF:

0.000535

GnomAD4 genome

AF:

0.000644

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00112

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000711

Hom.:

Bravo

AF:

0.000548

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00104

AC:

ExAC

AF:

0.000205

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 15, 2021

The c.3723T>G (p.C1241W) alteration is located in exon 18 (coding exon 18) of the VWDE gene. This alteration results from a T to G substitution at nucleotide position 3723, causing the cysteine (C) at amino acid position 1241 to be replaced by a tryptophan (W). 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

0.24

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

T;D;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.78

T;T;T

M_CAP

Benign

0.075

MetaRNN

Pathogenic

0.88

D;D;D

MetaSVM

Uncertain

0.30

MutationAssessor

Pathogenic

4.5

H;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-7.2

D;.;.

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0010

D;.;.

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.87

MVP

0.71

ClinPred

0.58

GERP RS

2.7

Varity_R

0.75

gMVP

0.93

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