rs1046314

chr4-6302228-G-Achr4-6302228-G-Cchr4-6302228-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006005.3(WFS1):c.2433G>A(p.Lys811=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.604 in 1,608,966 control chromosomes in the GnomAD database, including 298,167 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (27101 hom., cov: 34)
  • Exomes 𝑓: 0.61 (271066 hom.)
• Consequence: WFS1 NM_006005.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.19

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-6302228-G-A is Benign according to our data. Variant chr4-6302228-G-A is described in ClinVar as [Benign]. Clinvar id is 45455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6302228-G-A is described in Lovd as [Benign]. Variant chr4-6302228-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.19 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3	c.2433G>A	p.Lys811=	synonymous_variant	8/8	ENST00000226760.5
WFS1	NM_001145853.1	c.2433G>A	p.Lys811=	synonymous_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.2433G>A	p.Lys811=	synonymous_variant	8/8	1	NM_006005.3	P2
	ENST00000661896.1	n.1337+1687C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.587 AC: 89312 AN: 152030 Hom.: 27083 Cov.: 34

Gnomad AFR AF: 0.503

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.661

Gnomad EAS AF: 0.933

Gnomad SAS AF: 0.642

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.625

Gnomad NFE AF: 0.592

Gnomad OTH AF: 0.616

GnomAD3 exomes AF: 0.637 AC: 157797 AN: 247650 Hom.: 51643 AF XY: 0.635 AC XY: 85353 AN XY: 134344

Gnomad AFR exome AF: 0.504

Gnomad AMR exome AF: 0.736

Gnomad ASJ exome AF: 0.676

Gnomad EAS exome AF: 0.931

Gnomad SAS exome AF: 0.635

Gnomad FIN exome AF: 0.568

Gnomad NFE exome AF: 0.588

Gnomad OTH exome AF: 0.633

GnomAD4 exome AF: 0.606 AC: 882669 AN: 1456816 Hom.: 271066 Cov.: 101 AF XY: 0.607 AC XY: 439418 AN XY: 724210

Gnomad4 AFR exome AF: 0.502

Gnomad4 AMR exome AF: 0.728

Gnomad4 ASJ exome AF: 0.677

Gnomad4 EAS exome AF: 0.958

Gnomad4 SAS exome AF: 0.634

Gnomad4 FIN exome AF: 0.568

Gnomad4 NFE exome AF: 0.589

Gnomad4 OTH exome AF: 0.622

GnomAD4 genome AF: 0.587 AC: 89362 AN: 152150 Hom.: 27101 Cov.: 34 AF XY: 0.589 AC XY: 43796 AN XY: 74394

Gnomad4 AFR AF: 0.502

Gnomad4 AMR AF: 0.669

Gnomad4 ASJ AF: 0.661

Gnomad4 EAS AF: 0.933

Gnomad4 SAS AF: 0.643

Gnomad4 FIN AF: 0.562

Gnomad4 NFE AF: 0.592

Gnomad4 OTH AF: 0.618

Alfa AF: 0.595 Hom.: 29309

Bravo AF: 0.593

Asia WGS AF: 0.754 AC: 2624 AN: 3478

EpiCase AF: 0.593

EpiControl AF: 0.600

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 28, 2012	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 30, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 12107816) -
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	- -

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. -

Sensorineural hearing loss disorder Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Potent mutations of WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. Prevalence of rs1046314 is seen with sensoneural deafness. -

Diabetes mellitus Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Potent mutations of WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. rs1046314 is seen to be associated with Diabetes Mellitus. -

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
BayesDel_noAF	Benign	-0.81
Cadd	Benign	5.3
Dann	Benign	0.62

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: rs1046314; hg19: chr4-6303955; COSMIC: COSV56987318; COSMIC: COSV56987318;