rs1805069

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_006005.3(WFS1):c.1726G>A(p.Gly576Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00462 in 1,613,806 control chromosomes in the GnomAD database, including 213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.011 ( 25 hom., cov: 34)

Exomes 𝑓: 0.0040 ( 188 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications B:12O:1

Conservation

PhyloP100: 5.88

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005336702).

BP6

Variant 4-6301521-G-A is Benign according to our data. Variant chr4-6301521-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45439.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=7, Uncertain_risk_allele=1}. Variant chr4-6301521-G-A is described in Lovd as [Benign]. Variant chr4-6301521-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0652 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.1726G>A	p.Gly576Ser	missense_variant	8/8	ENST00000226760.5	NP_005996.2	O76024A0A0S2Z4V6
WFS1	NM_001145853.1 linkuse as main transcript	c.1726G>A	p.Gly576Ser	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.1726G>A	p.Gly576Ser	missense_variant	8/8	1	NM_006005.3	ENSP00000226760.1		O76024

Frequencies

GnomAD3 genomes

AF:

0.0110

AC:

1672

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0148

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0712

Gnomad SAS

AF:

0.00227

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.00954

AC:

2397

AN:

251166

Hom.:

AF XY:

0.00806

AC XY:

1095

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.0242

Gnomad AMR exome

AF:

0.0191

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.0670

Gnomad SAS exome

AF:

0.00150

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.00522

GnomAD4 exome

AF:

0.00396

AC:

5789

AN:

1461478

Hom.:

188

Cov.:

AF XY:

0.00374

AC XY:

2721

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.0235

Gnomad4 AMR exome

AF:

0.0185

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.0877

Gnomad4 SAS exome

AF:

0.00195

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.000224

Gnomad4 OTH exome

AF:

0.00431

GnomAD4 genome

AF:

0.0110

AC:

1674

AN:

152328

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

837

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0244

Gnomad4 AMR

AF:

0.0148

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0712

Gnomad4 SAS

AF:

0.00248

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.00290

Hom.:

Bravo

AF:

0.0135

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0186

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00892

AC:

1083

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Benign:12Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 06, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Gly576Ser in Exon 08 of WFS1: This variant is not expected to have clinical sign ificance because it has been identified in 1.9% (72/3738) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs1805069). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 23, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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. -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Feb 08, 2019

ACMG criteria: BA1 (6.7% in gnomAD SA, 2.3% in gnomAD African), BS2 (62 homozygotes in gnomAD)=Benign (REVEL 0.534 + precictor evidence not consistent, not using) -

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. -

Wolfram syndrome 1

Other:1

Uncertain risk allele, criteria provided, single submitter

research

Clinical 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 rs1805069 yet. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.67

.;T

MetaRNN

Benign

0.0053

T;T

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.8

N;N

REVEL

Uncertain

0.54

Sift

Benign

0.031

D;D

Sift4G

Uncertain

0.022

D;D

Polyphen

0.88

P;P

Vest4

0.65

MVP

0.99

ClinPred

0.027

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.76

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