Variant 7-12337017-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001135924.3(VWDE):c.4529C>G(p.Ser1510Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000142 in 1,551,374 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

VWDE
NM_001135924.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.03

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VWDE	NM_001135924.3 linkuse as main transcript	c.4529C>G	p.Ser1510Cys	missense_variant	26/29	ENST00000275358.8	NP_001129396.1
VWDE	NM_001346972.2 linkuse as main transcript	c.4184C>G	p.Ser1395Cys	missense_variant	24/27		NP_001333901.1
VWDE	NM_001346973.2 linkuse as main transcript	c.3719C>G	p.Ser1240Cys	missense_variant	24/27		NP_001333902.1
VWDE	NR_144534.2 linkuse as main transcript	n.5351C>G		non_coding_transcript_exon_variant	27/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWDE	ENST00000275358.8 linkuse as main transcript	c.4529C>G	p.Ser1510Cys	missense_variant	26/29	5	NM_001135924.3	ENSP00000275358	P1	Q8N2E2-1
VWDE	ENST00000452576.6 linkuse as main transcript	c.*1293C>G		3_prime_UTR_variant, NMD_transcript_variant	27/30	1		ENSP00000401687
VWDE	ENST00000521169.5 linkuse as main transcript	c.*2907C>G		3_prime_UTR_variant, NMD_transcript_variant	23/26	5		ENSP00000428810

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000136

AC:

AN:

1399214

Hom.:

Cov.:

AF XY:

0.0000130

AC XY:

AN XY:

690104

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000841

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:

0.0000139

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000491

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

Dec 17, 2023

The c.4529C>G (p.S1510C) alteration is located in exon 26 (coding exon 26) of the VWDE gene. This alteration results from a C to G substitution at nucleotide position 4529, causing the serine (S) at amino acid position 1510 to be replaced by a cysteine (C). 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

0.25

BayesDel_addAF

Benign

-0.0031

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.64

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.7

MutationTaster

Benign

0.99

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.32

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.65

MutPred

0.42

Loss of glycosylation at S1510 (P = 0.0127);

MVP

0.32

ClinPred

0.99

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.39

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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