chr4-6291313-A-C

Position:

chr4-6291313-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_006005.3(WFS1):c.577A>C(p.Lys193Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00371 in 1,613,240 control chromosomes in the GnomAD database, including 29 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 0.0027 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 28 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:17

Conservation

PhyloP100: 5.20

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01354751).

BP6

Variant 4-6291313-A-C is Benign according to our data. Variant chr4-6291313-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178654.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=8, Likely_risk_allele=1}. Variant chr4-6291313-A-C is described in Lovd as [Benign]. Variant chr4-6291313-A-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3 linkuse as main transcript	c.577A>C	p.Lys193Gln	missense_variant	5/8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1 linkuse as main transcript	c.577A>C	p.Lys193Gln	missense_variant	5/8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5 linkuse as main transcript	c.577A>C	p.Lys193Gln	missense_variant	5/8	1	NM_006005.3	ENSP00000226760	P2

Frequencies

GnomAD3 genomes

AF:

0.00267

AC:

405

AN:

151782

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000654

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00545

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00834

Gnomad FIN

AF:

0.000474

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00303

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00380

AC:

951

AN:

250524

Hom.:

AF XY:

0.00437

AC XY:

593

AN XY:

135570

show subpopulations

Gnomad AFR exome

AF:

0.000371

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.0102

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0123

Gnomad FIN exome

AF:

0.000608

Gnomad NFE exome

AF:

0.00338

Gnomad OTH exome

AF:

0.00458

GnomAD4 exome

AF:

0.00382

AC:

5578

AN:

1461340

Hom.:

Cov.:

AF XY:

0.00409

AC XY:

2973

AN XY:

726938

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.00110

Gnomad4 ASJ exome

AF:

0.0107

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0119

Gnomad4 FIN exome

AF:

0.000870

Gnomad4 NFE exome

AF:

0.00351

Gnomad4 OTH exome

AF:

0.00344

GnomAD4 genome

AF:

0.00265

AC:

403

AN:

151900

Hom.:

Cov.:

AF XY:

0.00296

AC XY:

220

AN XY:

74212

show subpopulations

Gnomad4 AFR

AF:

0.000652

Gnomad4 AMR

AF:

0.00544

Gnomad4 ASJ

AF:

0.0110

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00793

Gnomad4 FIN

AF:

0.000474

Gnomad4 NFE

AF:

0.00303

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00375

Hom.:

Bravo

AF:

0.00250

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00401

AC:

487

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00436

EpiControl

AF:

0.00409

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:17

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:8

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely 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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	WFS1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 22, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 31, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 30, 2013	p.Lys193Gln in exon 5 of WFS1: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% (30/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs41264699). -

Autosomal dominant nonsyndromic hearing loss 6

Benign:2

Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Lys193Gln variant in WFS1 has been identified in an individual with sensorineural hearing loss and in the compound heterozygous state in an individual with gait instability, optic atrophy, and cerebellar dysarthria (PMID: 12073007, 25497598), and has been identified in >1% of South Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal dominant sensorineural hearing loss. -
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. -

Wolfram syndrome 1

Pathogenic:1

Likely risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Feb 21, 2024

Mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. rs41264699 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained. This variant is found to be a potent moderate impact, deleterious variant with a CADD score of 24 and sufficient scientific evidence to support the reported classification. This is found more frequently in Wolfram syndrome cases as per recent evidence as well. -

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). 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. -

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

May 05, 2022

- -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Nov 21, 2018

ACMG criteria: BS1 (1.3% in gnomAD S Asian, 1% gnomAD AJ), BS2 (74 cases and 62 control in T2DM and 5 homozygotes in gnomAD)=benign (REVEL 0.223 + PP3/5 predictors + BP4/4 predictors: conflicting evidence, not using) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;T

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.82

.;T

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-0.38

MutationAssessor

Uncertain

2.1

M;M

MutationTaster

Benign

0.72

D;D

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.4

N;N

REVEL

Pathogenic

0.69

Sift

Benign

0.052

T;T

Sift4G

Benign

0.082

T;T

Polyphen

0.91

P;P

Vest4

0.69

MVP

1.0

ClinPred

0.031

GERP RS

3.4

Varity_R

0.19

gMVP

0.78

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