rs1801208

Positions:

chr4-6301162-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM5BP4_StrongBP6BA1

The ENST00000226760.5(WFS1):c.1367G>A(p.Arg456His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0518 in 1,612,200 control chromosomes in the GnomAD database, including 2,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R456C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.051 ( 233 hom., cov: 33)

Exomes 𝑓: 0.052 ( 2185 hom. )

Consequence

WFS1
ENST00000226760.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 9.34

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 -11 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-6301161-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.005521953).

BP6

Variant 4-6301162-G-A is Benign according to our data. Variant chr4-6301162-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45434.We mark this variant Likely_benign, oryginal submissions are: {Benign=7, Likely_benign=3, Uncertain_significance=1}. Variant chr4-6301162-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0897 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.1367G>A	p.Arg456His	missense_variant	8/8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1 linkuse as main transcript	c.1367G>A	p.Arg456His	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.1367G>A	p.Arg456His	missense_variant	8/8	1	NM_006005.3	ENSP00000226760	P2
	ENST00000661896.1 linkuse as main transcript	n.1337+2753C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0511

AC:

7773

AN:

152054

Hom.:

233

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0367

Gnomad AMI

AF:

0.0264

Gnomad AMR

AF:

0.0604

Gnomad ASJ

AF:

0.0395

Gnomad EAS

AF:

0.0967

Gnomad SAS

AF:

0.0633

Gnomad FIN

AF:

0.0821

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0493

Gnomad OTH

AF:

0.0537

GnomAD3 exomes

AF:

0.0567

AC:

14160

AN:

249686

Hom.:

449

AF XY:

0.0577

AC XY:

7796

AN XY:

135076

show subpopulations

Gnomad AFR exome

AF:

0.0367

Gnomad AMR exome

AF:

0.0577

Gnomad ASJ exome

AF:

0.0324

Gnomad EAS exome

AF:

0.0911

Gnomad SAS exome

AF:

0.0646

Gnomad FIN exome

AF:

0.0796

Gnomad NFE exome

AF:

0.0491

Gnomad OTH exome

AF:

0.0650

GnomAD4 exome

AF:

0.0519

AC:

75746

AN:

1460028

Hom.:

2185

Cov.:

103

AF XY:

0.0522

AC XY:

37887

AN XY:

726372

show subpopulations

Gnomad4 AFR exome

AF:

0.0393

Gnomad4 AMR exome

AF:

0.0611

Gnomad4 ASJ exome

AF:

0.0368

Gnomad4 EAS exome

AF:

0.101

Gnomad4 SAS exome

AF:

0.0637

Gnomad4 FIN exome

AF:

0.0781

Gnomad4 NFE exome

AF:

0.0480

Gnomad4 OTH exome

AF:

0.0570

GnomAD4 genome

AF:

0.0511

AC:

7777

AN:

152172

Hom.:

233

Cov.:

AF XY:

0.0526

AC XY:

3916

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0367

Gnomad4 AMR

AF:

0.0603

Gnomad4 ASJ

AF:

0.0395

Gnomad4 EAS

AF:

0.0967

Gnomad4 SAS

AF:

0.0635

Gnomad4 FIN

AF:

0.0821

Gnomad4 NFE

AF:

0.0493

Gnomad4 OTH

AF:

0.0546

Alfa

AF:

0.0507

Hom.:

393

Bravo

AF:

0.0503

TwinsUK

AF:

0.0502

AC:

186

ALSPAC

AF:

0.0451

AC:

174

ESP6500AA

AF:

0.0386

AC:

170

ESP6500EA

AF:

0.0508

AC:

437

ExAC

AF:

0.0569

AC:

6912

Asia WGS

AF:

0.0840

AC:

292

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Arg456His in Exon 08 of WFS1: This variant is not expected to have clinical sign ificance because it has been identified in 5.0% (352/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs1801208). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 04, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 02, 2013	- -

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 26284228, 10679252, 23595122, 25497598) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 02, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Wolfram syndrome 1

Uncertain:1

Uncertain significance, 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. rs1801208 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained. -

WFS1-Related Spectrum Disorders

Benign:1

Likely 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Autosomal dominant nonsyndromic hearing loss 6

Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;T

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;D

MetaRNN

Benign

0.0055

T;T

MetaSVM

Benign

-0.31

MutationAssessor

Uncertain

2.8

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.3

N;N

REVEL

Uncertain

0.53

Sift

Benign

0.080

T;T

Sift4G

Uncertain

0.011

D;D

Polyphen

1.0

D;D

Vest4

0.31

ClinPred

0.053

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.80

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