Variant chr7-12340344-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001135924.3(VWDE):c.4344C>A(p.Phe1448Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000258 in 1,550,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

VWDE
NM_001135924.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.29

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38818705).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VWDE	NM_001135924.3 linkuse as main transcript	c.4344C>A	p.Phe1448Leu	missense_variant	24/29	ENST00000275358.8	NP_001129396.1
VWDE	NM_001346972.2 linkuse as main transcript	c.3999C>A	p.Phe1333Leu	missense_variant	22/27		NP_001333901.1
VWDE	NM_001346973.2 linkuse as main transcript	c.3534C>A	p.Phe1178Leu	missense_variant	22/27		NP_001333902.1
VWDE	NR_144534.2 linkuse as main transcript	n.5166C>A		non_coding_transcript_exon_variant	25/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWDE	ENST00000275358.8 linkuse as main transcript	c.4344C>A	p.Phe1448Leu	missense_variant	24/29	5	NM_001135924.3	ENSP00000275358	P1	Q8N2E2-1
VWDE	ENST00000452576.6 linkuse as main transcript	c.*1108C>A		3_prime_UTR_variant, NMD_transcript_variant	25/30	1		ENSP00000401687
VWDE	ENST00000521169.5 linkuse as main transcript	c.*2722C>A		3_prime_UTR_variant, NMD_transcript_variant	21/26	5		ENSP00000428810

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1398902

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689962

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:

0.0000253

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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

Alfa

AF:

0.0000658

Hom.:

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2024

The c.4344C>A (p.F1448L) alteration is located in exon 24 (coding exon 24) of the VWDE gene. This alteration results from a C to A substitution at nucleotide position 4344, causing the phenylalanine (F) at amino acid position 1448 to be replaced by a leucine (L). 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

Pathogenic

0.94

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.039

T;T

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.79

T;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.39

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.3

M;.

MutationTaster

Benign

0.98

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-4.0

D;.

REVEL

Benign

0.21

Sift

Uncertain

0.011

D;.

Sift4G

Uncertain

0.0050

D;D

Polyphen

0.99

D;.

Vest4

0.50

MutPred

0.71

Gain of relative solvent accessibility (P = 0.1259);.;

MVP

0.081

ClinPred

0.99

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.38

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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