rs41264699

chr4-6291313-A-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K193R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (28 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:16
• Conservation: PhyloP100: 5.20

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_006005.3
• 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=4, 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 GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3	c.577A>C	p.Lys193Gln	missense_variant	5/8	ENST00000226760.5
WFS1	NM_001145853.1	c.577A>C	p.Lys193Gln	missense_variant	5/8

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00267 AC: 405 AN: 151782 Hom.: 1 Cov.: 32

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.: 5 AF XY: 0.00437 AC XY: 593 AN XY: 135570

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.: 28 Cov.: 35 AF XY: 0.00409 AC XY: 2973 AN XY: 726938

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.: 1 Cov.: 32 AF XY: 0.00296 AC XY: 220 AN XY: 74212

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.: 2

Bravo AF: 0.00250

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00401 AC: 487

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00436

EpiControl AF: 0.00409

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:16

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:7

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
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, 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	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Benign:4

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). -
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	- -

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	T
BayesDel_noAF	Pathogenic	0.27
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.85	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	0.72	D;D
PrimateAI	Uncertain	0.60	T
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	T
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

Other links and lift over

dbSNP: rs41264699; hg19: chr4-6293040;