rs734312

Positions:

• chr4-6301627-G-A
• chr4-6301627-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BA1

The NM_006005.3(WFS1):​c.1832G>A​(p.Arg611His) variant causes a missense change. The variant allele was found at a frequency of 0.533 in 1,613,864 control chromosomes in the GnomAD database, including 240,154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R611C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.43 (17727 hom., cov: 33)
  • Exomes 𝑓: 0.54 (222427 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 4.92

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-6301625-GCG-GTA is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=2.282324E-6).
• BP6: Variant 4-6301627-G-A is Benign according to our data. Variant chr4-6301627-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 45442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6301627-G-A is described in Lovd as [Benign]. Variant chr4-6301627-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.802 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3	c.1832G>A	p.Arg611His	missense_variant	8/8	ENST00000226760.5
WFS1	NM_001145853.1	c.1832G>A	p.Arg611His	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.1832G>A	p.Arg611His	missense_variant	8/8	1	NM_006005.3	P2
	ENST00000661896.1	n.1337+2288C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.432 AC: 65710 AN: 152006 Hom.: 17718 Cov.: 33

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.822

Gnomad SAS AF: 0.574

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.471

GnomAD3 exomes AF: 0.552 AC: 138753 AN: 251300 Hom.: 41050 AF XY: 0.557 AC XY: 75651 AN XY: 135828

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.656

Gnomad ASJ exome AF: 0.644

Gnomad EAS exome AF: 0.833

Gnomad SAS exome AF: 0.568

Gnomad FIN exome AF: 0.489

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.551

GnomAD4 exome AF: 0.544 AC: 794851 AN: 1461740 Hom.: 222427 Cov.: 97 AF XY: 0.546 AC XY: 396845 AN XY: 727158

Gnomad4 AFR exome AF: 0.0885

Gnomad4 AMR exome AF: 0.641

Gnomad4 ASJ exome AF: 0.640

Gnomad4 EAS exome AF: 0.846

Gnomad4 SAS exome AF: 0.568

Gnomad4 FIN exome AF: 0.490

Gnomad4 NFE exome AF: 0.542

Gnomad4 OTH exome AF: 0.539

GnomAD4 genome AF: 0.432 AC: 65726 AN: 152124 Hom.: 17727 Cov.: 33 AF XY: 0.436 AC XY: 32442 AN XY: 74346

Gnomad4 AFR AF: 0.109

Gnomad4 AMR AF: 0.561

Gnomad4 ASJ AF: 0.622

Gnomad4 EAS AF: 0.822

Gnomad4 SAS AF: 0.575

Gnomad4 FIN AF: 0.481

Gnomad4 NFE AF: 0.543

Gnomad4 OTH AF: 0.473

Alfa AF: 0.532 Hom.: 53924

Bravo AF: 0.425

TwinsUK AF: 0.535 AC: 1982

ALSPAC AF: 0.543 AC: 2092

ESP6500AA AF: 0.117 AC: 515

ESP6500EA AF: 0.547 AC: 4703

ExAC AF: 0.536 AC: 65132

Asia WGS AF: 0.645 AC: 2243 AN: 3478

EpiCase AF: 0.541

EpiControl AF: 0.545

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 30, 2013	- -
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	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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 28, 2012	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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: 24477584, 23257691, 30232070, 27398621, 10679252, 19328217, 17719176, 24464100, 23595122, 12707947) -

Wolfram syndrome 1 Benign:2

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. rs734312 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

WFS1-Related Spectrum Disorders Benign:1

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Autosomal dominant nonsyndromic hearing loss 6 Benign:1

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.0000023	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	0.00066	P;P
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.49
Sift	Benign	0.085	T;T
Sift4G	Benign	0.066	T;T
Polyphen		0.15	B;B
Vest4		0.13
ClinPred		0.018	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.056
gMVP		0.90

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: rs734312; hg19: chr4-6303354; COSMIC: COSV56987772; COSMIC: COSV56987772;