4-6301914-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_006005.3(WFS1):​c.2119G>T​(p.Val707Phe) variant causes a missense change. 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: 34)

Consequence

WFS1
NM_006005.3 missense

Scores

10
8
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.15
Variant links:
Genes affected
WFS1 (HGNC:12762): (wolframin ER transmembrane glycoprotein) This gene encodes a transmembrane protein, which is located primarily in the endoplasmic reticulum and ubiquitously expressed with highest levels in brain, pancreas, heart, and insulinoma beta-cell lines. Mutations in this gene are associated with Wolfram syndrome, also called DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness), an autosomal recessive disorder. The disease affects the brain and central nervous system. Mutations in this gene can also cause autosomal dominant deafness 6 (DFNA6), also known as DFNA14 or DFNA38. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a topological_domain Lumenal (size 216) in uniprot entity WFS1_HUMAN there are 92 pathogenic changes around while only 24 benign (79%) in NM_006005.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
WFS1NM_006005.3 linkc.2119G>T p.Val707Phe missense_variant Exon 8 of 8 ENST00000226760.5 NP_005996.2 O76024A0A0S2Z4V6
WFS1NM_001145853.1 linkc.2119G>T p.Val707Phe missense_variant Exon 8 of 8 NP_001139325.1 O76024A0A0S2Z4V6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
WFS1ENST00000226760.5 linkc.2119G>T p.Val707Phe missense_variant Exon 8 of 8 1 NM_006005.3 ENSP00000226760.1 O76024

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Cov.:
99
GnomAD4 genome
Cov.:
34

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Mar 25, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt WFS1 protein function. ClinVar contains an entry for this variant (Variation ID: 30552). This missense change has been observed in individual(s) with autosomal dominant hearing loss (PMID: 32382995; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 707 of the WFS1 protein (p.Val707Phe). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.51
CADD
Uncertain
26
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.76
D;D
Eigen
Pathogenic
0.71
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
.;D
M_CAP
Pathogenic
0.88
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.8
M;M
PrimateAI
Uncertain
0.71
T
PROVEAN
Uncertain
-4.1
D;D
REVEL
Pathogenic
0.91
Sift
Uncertain
0.0020
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.92
MutPred
0.78
Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP
0.99
ClinPred
0.99
D
GERP RS
5.5
Varity_R
0.75
gMVP
0.95

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs71524377; hg19: chr4-6303641; API