rs1801212

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006005.3(WFS1):c.997G>A(p.Val333Ile) variant causes a missense change. The variant allele was found at a frequency of 0.749 in 1,613,806 control chromosomes in the GnomAD database, including 457,955 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict 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. V333F) has been classified as Benign.

Frequency

Genomes: 𝑓 0.80 ( 50072 hom., cov: 30)

Exomes 𝑓: 0.74 ( 407883 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.07

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:

WFS1 (HGNC:):

WFS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.7407621E-6).

BP6

Variant 4-6300792-G-A is Benign according to our data. Variant chr4-6300792-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 45463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6300792-G-A is described in Lovd as [Benign]. Variant chr4-6300792-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 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.997G>A	p.Val333Ile	missense_variant	8/8	ENST00000226760.5	NP_005996.2	O76024A0A0S2Z4V6
WFS1	NM_001145853.1 linkuse as main transcript	c.997G>A	p.Val333Ile	missense_variant	8/8		NP_001139325.1	O76024A0A0S2Z4V6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5 linkuse as main transcript	c.997G>A	p.Val333Ile	missense_variant	8/8	1	NM_006005.3	ENSP00000226760.1		O76024

Frequencies

GnomAD3 genomes

AF:

0.804

AC:

122007

AN:

151814

Hom.:

50011

Cov.:

show subpopulations

Gnomad AFR

AF:

0.952

Gnomad AMI

AF:

0.586

Gnomad AMR

AF:

0.801

Gnomad ASJ

AF:

0.810

Gnomad EAS

AF:

0.996

Gnomad SAS

AF:

0.848

Gnomad FIN

AF:

0.661

Gnomad MID

AF:

0.832

Gnomad NFE

AF:

0.721

Gnomad OTH

AF:

0.788

GnomAD3 exomes

AF:

0.781

AC:

196436

AN:

251462

Hom.:

77879

AF XY:

0.778

AC XY:

105782

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.955

Gnomad AMR exome

AF:

0.809

Gnomad ASJ exome

AF:

0.814

Gnomad EAS exome

AF:

0.998

Gnomad SAS exome

AF:

0.840

Gnomad FIN exome

AF:

0.664

Gnomad NFE exome

AF:

0.717

Gnomad OTH exome

AF:

0.768

GnomAD4 exome

AF:

0.744

AC:

1087224

AN:

1461872

Hom.:

407883

Cov.:

AF XY:

0.746

AC XY:

542183

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.961

Gnomad4 AMR exome

AF:

0.808

Gnomad4 ASJ exome

AF:

0.812

Gnomad4 EAS exome

AF:

0.998

Gnomad4 SAS exome

AF:

0.834

Gnomad4 FIN exome

AF:

0.665

Gnomad4 NFE exome

AF:

0.719

Gnomad4 OTH exome

AF:

0.775

GnomAD4 genome

AF:

0.804

AC:

122131

AN:

151934

Hom.:

50072

Cov.:

AF XY:

0.803

AC XY:

59635

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.952

Gnomad4 AMR

AF:

0.801

Gnomad4 ASJ

AF:

0.810

Gnomad4 EAS

AF:

0.996

Gnomad4 SAS

AF:

0.847

Gnomad4 FIN

AF:

0.661

Gnomad4 NFE

AF:

0.721

Gnomad4 OTH

AF:

0.791

Alfa

AF:

0.744

Hom.:

107108

Bravo

AF:

0.820

TwinsUK

AF:

0.714

AC:

2649

ALSPAC

AF:

0.716

AC:

2759

ESP6500AA

AF:

0.947

AC:

4172

ESP6500EA

AF:

0.724

AC:

6224

ExAC

AF:

0.782

AC:

94911

Asia WGS

AF:

0.929

AC:

3229

AN:

3476

EpiCase

AF:

0.725

EpiControl

AF:

0.732

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

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 27, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 30, 2013	- -

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 31118516, 25740874, 29632382, 27398621, 21726277, 24464100, 21517693) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

WFS1-Related Spectrum Disorders

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Type 2 diabetes mellitus;C1833021:Autosomal dominant nonsyndromic hearing loss 6;C3280358:Wolfram-like syndrome;C3805412:Cataract 41;C4551693:Wolfram syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 30, 2022

- -

Autosomal dominant nonsyndromic hearing loss 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

Wolfram syndrome 1

Benign:1

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. rs1801212 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.56

DEOGEN2

Benign

0.10

T;T

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.57

.;T

MetaRNN

Benign

0.0000017

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-2.8

N;N

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.36

N;N

REVEL

Benign

0.22

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0010

B;B

Vest4

0.070

ClinPred

0.0027

GERP RS

3.4

Varity_R

0.036

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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