7-12333539-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001135924.3(VWDE):​c.4684G>C​(p.Gly1562Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

VWDE
NM_001135924.3 missense

Scores

12
4
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.67
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.879

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VWDENM_001135924.3 linkc.4684G>C p.Gly1562Arg missense_variant Exon 28 of 29 ENST00000275358.8 NP_001129396.1 Q8N2E2-1
VWDENM_001346972.2 linkc.4339G>C p.Gly1447Arg missense_variant Exon 26 of 27 NP_001333901.1
VWDENM_001346973.2 linkc.3874G>C p.Gly1292Arg missense_variant Exon 26 of 27 NP_001333902.1
VWDENR_144534.2 linkn.5506G>C non_coding_transcript_exon_variant Exon 29 of 30

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VWDEENST00000275358.8 linkc.4684G>C p.Gly1562Arg missense_variant Exon 28 of 29 5 NM_001135924.3 ENSP00000275358.3 Q8N2E2-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 09, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.4684G>C (p.G1562R) alteration is located in exon 28 (coding exon 28) of the VWDE gene. This alteration results from a G to C substitution at nucleotide position 4684, causing the glycine (G) at amino acid position 1562 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
Pathogenic
0.74
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.42
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.087
T
Eigen
Pathogenic
0.71
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.96
D
M_CAP
Pathogenic
0.53
D
MetaRNN
Pathogenic
0.88
D
MetaSVM
Pathogenic
1.2
D
MutationAssessor
Pathogenic
3.9
H
PrimateAI
Benign
0.43
T
PROVEAN
Pathogenic
-4.8
D
REVEL
Pathogenic
0.73
Sift
Uncertain
0.0030
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.58
MutPred
0.70
Loss of stability (P = 0.1462);
MVP
0.83
ClinPred
1.0
D
GERP RS
4.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.50
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-12373165; API