rs1046314

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 1.19

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
WFS1	NM_006005.3 linkuse as main transcript	c.2433G>A	p.Lys811=	synonymous_variant	8/8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1 linkuse as main transcript	c.2433G>A	p.Lys811=	synonymous_variant	8/8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5 linkuse as main transcript	c.2433G>A	p.Lys811=	synonymous_variant	8/8	1	NM_006005.3	ENSP00000226760	P2
	ENST00000661896.1 linkuse as main transcript	n.1337+1687C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.587

AC:

89312

AN:

152030

Hom.:

27083

Cov.:

show subpopulations

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

show subpopulations

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

show subpopulations

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.:

AF XY:

0.589

AC XY:

43796

AN XY:

74394

show subpopulations

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:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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

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

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