rs150894674

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 4P and 12B. PM1PM2BP4_StrongBP6_Very_Strong

The NM_006005.3(WFS1):​c.1321G>A​(p.Val441Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,613,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

1
5
13

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.73
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_006005.3
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.016420841).
BP6
Variant 4-6301116-G-A is Benign according to our data. Variant chr4-6301116-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
WFS1NM_006005.3 linkuse as main transcriptc.1321G>A p.Val441Met missense_variant 8/8 ENST00000226760.5
WFS1NM_001145853.1 linkuse as main transcriptc.1321G>A p.Val441Met missense_variant 8/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
WFS1ENST00000226760.5 linkuse as main transcriptc.1321G>A p.Val441Met missense_variant 8/81 NM_006005.3 P2
ENST00000661896.1 linkuse as main transcriptn.1337+2799C>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.000881
AC:
134
AN:
152076
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00295
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.000263
AC:
66
AN:
250864
Hom.:
0
AF XY:
0.000221
AC XY:
30
AN XY:
135614
show subpopulations
Gnomad AFR exome
AF:
0.00289
Gnomad AMR exome
AF:
0.000405
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000652
GnomAD4 exome
AF:
0.0000876
AC:
128
AN:
1461362
Hom.:
0
Cov.:
103
AF XY:
0.0000770
AC XY:
56
AN XY:
726996
show subpopulations
Gnomad4 AFR exome
AF:
0.00260
Gnomad4 AMR exome
AF:
0.000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.000215
GnomAD4 genome
AF:
0.000867
AC:
132
AN:
152194
Hom.:
0
Cov.:
33
AF XY:
0.000847
AC XY:
63
AN XY:
74410
show subpopulations
Gnomad4 AFR
AF:
0.00289
Gnomad4 AMR
AF:
0.000458
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.000148
Hom.:
1
Bravo
AF:
0.00105
ESP6500AA
AF:
0.00295
AC:
13
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000288
AC:
35
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
Likely benign, criteria provided, single submitterclinical testingGeneDxFeb 18, 2020This variant is associated with the following publications: (PMID: 11244483) -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 30, 2012Val441Met in Exon 08 of WFS1: This variant is not expected to have clinical sign ificance because it has been identified in 0.4% (14/3738) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs150894674). -
WFS1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesDec 01, 2022This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Wolfram syndrome 1 Benign:1
Likely benign, criteria provided, single submitterresearchClinical Genomics, Uppaluri K&H Personalized Medicine Clinic-Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. However no sufficient evidence is found to ascertain the role of this particular variant rs150894674 in Wolfram's syndrome yet. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
16
DANN
Uncertain
1.0
DEOGEN2
Benign
0.083
T;T
Eigen
Benign
-0.21
Eigen_PC
Benign
-0.25
FATHMM_MKL
Benign
0.45
N
LIST_S2
Uncertain
0.95
.;D
M_CAP
Pathogenic
0.36
D
MetaRNN
Benign
0.016
T;T
MetaSVM
Benign
-0.31
T
MutationAssessor
Uncertain
2.2
M;M
MutationTaster
Benign
0.96
N;N
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-0.36
N;N
REVEL
Uncertain
0.32
Sift
Benign
0.29
T;T
Sift4G
Uncertain
0.037
D;D
Polyphen
0.74
P;P
Vest4
0.28
MVP
0.90
ClinPred
0.0092
T
GERP RS
3.8
Varity_R
0.028
gMVP
0.66

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: rs150894674; hg19: chr4-6302843; COSMIC: COSV56992164; COSMIC: COSV56992164; API