Genetic Variant VWDE:p.Gly1354Arg (chr7-12344213-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001135924.3(VWDE):c.4060G>A(p.Gly1354Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,550,412 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

VWDE
NM_001135924.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.83

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 Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWDE	NM_001135924.3 link	c.4060G>A	p.Gly1354Arg	missense_variant	Exon 21 of 29	ENST00000275358.8	NP_001129396.1	Q8N2E2-1
VWDE	NM_001346972.2 link	c.3715G>A	p.Gly1239Arg	missense_variant	Exon 19 of 27		NP_001333901.1
VWDE	NM_001346973.2 link	c.3250G>A	p.Gly1084Arg	missense_variant	Exon 19 of 27		NP_001333902.1
VWDE	NR_144534.2 link	n.4882G>A		non_coding_transcript_exon_variant	Exon 22 of 30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWDE	ENST00000275358.8 link	c.4060G>A	p.Gly1354Arg	missense_variant	Exon 21 of 29	5	NM_001135924.3	ENSP00000275358.3		Q8N2E2-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151924

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.0000127

AC:

AN:

157056

Hom.:

AF XY:

0.0000241

AC XY:

AN XY:

83026

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000328

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000129

AC:

AN:

1398488

Hom.:

Cov.:

AF XY:

0.0000101

AC XY:

AN XY:

689768

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000148

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151924

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74194

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4060G>A (p.G1354R) alteration is located in exon 21 (coding exon 21) of the VWDE gene. This alteration results from a G to A substitution at nucleotide position 4060, causing the glycine (G) at amino acid position 1354 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

Benign

0.29

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;T

Eigen

Pathogenic

0.82

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.78

T;T

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

3.7

H;.

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-4.4

D;.

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0050

D;.

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.84

MutPred

0.93

Gain of relative solvent accessibility (P = 0.0483);.;

MVP

0.69

ClinPred

0.99

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.37

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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