Genetic Variant VWDE:p.Gly1479Val (chr7-12337203-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001135924.3(VWDE):c.4436G>T(p.Gly1479Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,399,642 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: not found (cov: 33)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

VWDE
NM_001135924.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.41

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.796

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135924.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VWDE	NM_001135924.3	MANE Select	c.4436G>T	p.Gly1479Val	missense	Exon 25 of 29	NP_001129396.1	Q8N2E2-1
VWDE	NM_001346972.2		c.4091G>T	p.Gly1364Val	missense	Exon 23 of 27	NP_001333901.1
VWDE	NM_001346973.2		c.3626G>T	p.Gly1209Val	missense	Exon 23 of 27	NP_001333902.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VWDE	ENST00000275358.8	TSL:5 MANE Select	c.4436G>T	p.Gly1479Val	missense	Exon 25 of 29	ENSP00000275358.3	Q8N2E2-1
VWDE	ENST00000452576.6	TSL:1	n.*1200G>T		non_coding_transcript_exon	Exon 26 of 30	ENSP00000401687.2	J3KQJ9
VWDE	ENST00000452576.6	TSL:1	n.*1200G>T		3_prime_UTR	Exon 26 of 30	ENSP00000401687.2	J3KQJ9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000634

AC:

AN:

157704

AF XY:

0.0000120

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000286

AC:

AN:

1399642

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

690314

show subpopulations

African (AFR)

AF:

0.0000949

AC:

AN:

31598

American (AMR)

AF:

0.00

AC:

AN:

35706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25180

East Asian (EAS)

AF:

0.00

AC:

AN:

35732

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079004

Other (OTH)

AF:

0.00

AC:

AN:

58078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.066

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.047

MetaRNN

Pathogenic

0.80

MetaSVM

Uncertain

-0.16

MutationAssessor

Pathogenic

4.3

PhyloP100

7.4

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-6.8

REVEL

Uncertain

0.53

Sift

Uncertain

0.010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.81

MutPred

0.52

Loss of disorder (P = 0.0534)

MVP

0.43

ClinPred

1.0

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.79

gMVP

0.89

Mutation Taster

=62/38

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over