rs71530923

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006005.3(WFS1):ā€‹c.124C>Gā€‹(p.Arg42Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000568 in 1,583,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 34)
Exomes š‘“: 0.0000056 ( 0 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.594
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.11564487).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WFS1NM_006005.3 linkuse as main transcriptc.124C>G p.Arg42Gly missense_variant 2/8 ENST00000226760.5 NP_005996.2
WFS1NM_001145853.1 linkuse as main transcriptc.124C>G p.Arg42Gly missense_variant 2/8 NP_001139325.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WFS1ENST00000226760.5 linkuse as main transcriptc.124C>G p.Arg42Gly missense_variant 2/81 NM_006005.3 ENSP00000226760 P2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152230
Hom.:
0
Cov.:
34
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:
0.00316
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000559
AC:
8
AN:
1431560
Hom.:
0
Cov.:
33
AF XY:
0.00000282
AC XY:
2
AN XY:
709028
show subpopulations
Gnomad4 AFR exome
AF:
0.0000912
Gnomad4 AMR exome
AF:
0.0000246
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000364
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000656
AC:
1
AN:
152348
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
74510
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:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 28, 2023This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 42 of the WFS1 protein (p.Arg42Gly). This variant has not been reported in the literature in individuals affected with WFS1-related conditions. 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 not expected to disrupt WFS1 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.058
BayesDel_addAF
Benign
-0.056
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
7.3
DANN
Benign
0.91
DEOGEN2
Benign
0.089
T;T
Eigen
Benign
-0.83
Eigen_PC
Benign
-0.90
FATHMM_MKL
Benign
0.040
N
LIST_S2
Benign
0.67
.;T
M_CAP
Benign
0.066
D
MetaRNN
Benign
0.12
T;T
MetaSVM
Uncertain
-0.19
T
MutationAssessor
Uncertain
2.2
M;M
MutationTaster
Benign
1.0
N;N
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-1.2
N;N
REVEL
Benign
0.10
Sift
Uncertain
0.026
D;D
Sift4G
Benign
0.19
T;T
Polyphen
0.0010
B;B
Vest4
0.24
MutPred
0.17
Loss of solvent accessibility (P = 0.0044);Loss of solvent accessibility (P = 0.0044);
MVP
0.73
ClinPred
0.092
T
GERP RS
2.4
Varity_R
0.065
gMVP
0.26

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: rs71530923; hg19: chr4-6279306; API