rs734312

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBA1

The NM_006005.3(WFS1):c.1832G>A(p.Arg611His) variant causes a missense change. The variant allele was found at a frequency of 0.533 in 1,613,864 control chromosomes in the GnomAD database, including 240,154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R611Y) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.43 ( 17727 hom., cov: 33)

Exomes 𝑓: 0.54 ( 222427 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 4.92

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]

WFS1 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-6301625-GCG-GTA is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=2.282324E-6).

BP6

Variant 4-6301627-G-A is Benign according to our data. Variant chr4-6301627-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 45442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6301627-G-A is described in Lovd as [Benign]. Variant chr4-6301627-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.802 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3 linkuse as main transcript	c.1832G>A	p.Arg611His	missense_variant	8/8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1 linkuse as main transcript	c.1832G>A	p.Arg611His	missense_variant	8/8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5 linkuse as main transcript	c.1832G>A	p.Arg611His	missense_variant	8/8	1	NM_006005.3	ENSP00000226760	P2
	ENST00000661896.1 linkuse as main transcript	n.1337+2288C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.432

AC:

65710

AN:

152006

Hom.:

17718

Cov.:

show subpopulations

Gnomad AFR

AF:

0.109

Gnomad AMI

AF:

0.364

Gnomad AMR

AF:

0.561

Gnomad ASJ

AF:

0.622

Gnomad EAS

AF:

0.822

Gnomad SAS

AF:

0.574

Gnomad FIN

AF:

0.481

Gnomad MID

AF:

0.503

Gnomad NFE

AF:

0.543

Gnomad OTH

AF:

0.471

GnomAD3 exomes

AF:

0.552

AC:

138753

AN:

251300

Hom.:

41050

AF XY:

0.557

AC XY:

75651

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.102

Gnomad AMR exome

AF:

0.656

Gnomad ASJ exome

AF:

0.644

Gnomad EAS exome

AF:

0.833

Gnomad SAS exome

AF:

0.568

Gnomad FIN exome

AF:

0.489

Gnomad NFE exome

AF:

0.539

Gnomad OTH exome

AF:

0.551

GnomAD4 exome

AF:

0.544

AC:

794851

AN:

1461740

Hom.:

222427

Cov.:

AF XY:

0.546

AC XY:

396845

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.0885

Gnomad4 AMR exome

AF:

0.641

Gnomad4 ASJ exome

AF:

0.640

Gnomad4 EAS exome

AF:

0.846

Gnomad4 SAS exome

AF:

0.568

Gnomad4 FIN exome

AF:

0.490

Gnomad4 NFE exome

AF:

0.542

Gnomad4 OTH exome

AF:

0.539

GnomAD4 genome

AF:

0.432

AC:

65726

AN:

152124

Hom.:

17727

Cov.:

AF XY:

0.436

AC XY:

32442

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.109

Gnomad4 AMR

AF:

0.561

Gnomad4 ASJ

AF:

0.622

Gnomad4 EAS

AF:

0.822

Gnomad4 SAS

AF:

0.575

Gnomad4 FIN

AF:

0.481

Gnomad4 NFE

AF:

0.543

Gnomad4 OTH

AF:

0.473

Alfa

AF:

0.532

Hom.:

53924

Bravo

AF:

0.425

TwinsUK

AF:

0.535

AC:

1982

ALSPAC

AF:

0.543

AC:

2092

ESP6500AA

AF:

0.117

AC:

515

ESP6500EA

AF:

0.547

AC:

4703

ExAC

AF:

0.536

AC:

65132

Asia WGS

AF:

0.645

AC:

2243

AN:

3478

EpiCase

AF:

0.541

EpiControl

AF:

0.545

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 28, 2012	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 30, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24477584, 23257691, 30232070, 27398621, 10679252, 19328217, 17719176, 24464100, 23595122, 12707947) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Wolfram syndrome 1

Benign:2

Likely benign, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	Mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. rs734312 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

WFS1-Related Spectrum Disorders

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Autosomal dominant nonsyndromic hearing loss 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

T;T

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.11

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.84

.;T

MetaRNN

Benign

0.0000023

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

0.00066

P;P

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.8

N;N

REVEL

Uncertain

0.49

Sift

Benign

0.085

T;T

Sift4G

Benign

0.066

T;T

Polyphen

0.15

B;B

Vest4

0.13

ClinPred

0.018

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.056

gMVP

0.90

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over