7-12344443-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001135924.3(VWDE):c.3913A>C(p.Ser1305Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000236 in 1,550,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

VWDE
NM_001135924.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.16

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10906944).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
VWDE	NM_001135924.3 linkuse as main transcript	c.3913A>C	p.Ser1305Arg	missense_variant	20/29	ENST00000275358.8
VWDE	NM_001346972.2 linkuse as main transcript	c.3568A>C	p.Ser1190Arg	missense_variant	18/27
VWDE	NM_001346973.2 linkuse as main transcript	c.3103A>C	p.Ser1035Arg	missense_variant	18/27
VWDE	NR_144534.2 linkuse as main transcript	n.4735A>C		non_coding_transcript_exon_variant	21/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWDE	ENST00000275358.8 linkuse as main transcript	c.3913A>C	p.Ser1305Arg	missense_variant	20/29	5	NM_001135924.3	P1	Q8N2E2-1
VWDE	ENST00000452576.6 linkuse as main transcript	c.*677A>C		3_prime_UTR_variant, NMD_transcript_variant	21/30	1
VWDE	ENST00000649524.1 linkuse as main transcript	c.391A>C	p.Ser131Arg	missense_variant	3/3
VWDE	ENST00000521169.5 linkuse as main transcript	c.*2291A>C		3_prime_UTR_variant, NMD_transcript_variant	17/26	5

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

151948

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

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:

0.000221

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000110

AC:

AN:

155094

Hom.:

AF XY:

0.0000852

AC XY:

AN XY:

82146

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000205

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:

0.000200

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000246

AC:

344

AN:

1398074

Hom.:

Cov.:

AF XY:

0.000220

AC XY:

152

AN XY:

689512

show subpopulations

Gnomad4 AFR exome

AF:

0.0000951

Gnomad4 AMR exome

AF:

0.000140

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000203

Gnomad4 NFE exome

AF:

0.000305

Gnomad4 OTH exome

AF:

0.000104

GnomAD4 genome

AF:

0.000145

AC:

AN:

151948

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.0000484

Gnomad4 AMR

AF:

0.000328

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.000144

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

May 04, 2022

The c.3913A>C (p.S1305R) alteration is located in exon 20 (coding exon 20) of the VWDE gene. This alteration results from a A to C substitution at nucleotide position 3913, causing the serine (S) at amino acid position 1305 to be replaced by an arginine (R). 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

Uncertain

0.41

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.51

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.022

T;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.49

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;.

MutationTaster

Benign

0.99

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.3

N;.

REVEL

Benign

0.043

Sift

Benign

0.033

D;.

Sift4G

Uncertain

0.026

D;D

Polyphen

0.50

P;.

Vest4

0.21

MutPred

0.43

Loss of ubiquitination at K1304 (P = 0.0273);.;

MVP

0.15

ClinPred

0.11

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.095

gMVP

0.66

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