4-6291969-C-G

Position:

• chr4-6291969-C-G

Variant summary

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

The ENST00000226760.5(WFS1):​c.684C>G​(p.Arg228=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.691 in 1,608,700 control chromosomes in the GnomAD database, including 387,335 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (36573 hom., cov: 35)
  • Exomes 𝑓: 0.69 (350762 hom.)
• Consequence: WFS1 ENST00000226760.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.0700

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 4-6291969-C-G is Benign according to our data. Variant chr4-6291969-C-G is described in ClinVar as [Benign]. Clinvar id is 45460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6291969-C-G is described in Lovd as [Benign]. Variant chr4-6291969-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.914 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.684C>G	p.Arg228=	synonymous_variant	6/8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.684C>G	p.Arg228=	synonymous_variant	6/8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.684C>G	p.Arg228=	synonymous_variant	6/8	1	NM_006005.3	ENSP00000226760	P2

Frequencies

GnomAD3 genomes AF: 0.690 AC: 104906 AN: 152096 Hom.: 36540 Cov.: 35

Gnomad AFR AF: 0.671

Gnomad AMI AF: 0.571

Gnomad AMR AF: 0.744

Gnomad ASJ AF: 0.780

Gnomad EAS AF: 0.935

Gnomad SAS AF: 0.773

Gnomad FIN AF: 0.597

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.675

Gnomad OTH AF: 0.704

GnomAD3 exomes AF: 0.717 AC: 172276 AN: 240328 Hom.: 62580 AF XY: 0.717 AC XY: 93474 AN XY: 130454

Gnomad AFR exome AF: 0.675

Gnomad AMR exome AF: 0.781

Gnomad ASJ exome AF: 0.787

Gnomad EAS exome AF: 0.932

Gnomad SAS exome AF: 0.765

Gnomad FIN exome AF: 0.602

Gnomad NFE exome AF: 0.669

Gnomad OTH exome AF: 0.713

GnomAD4 exome AF: 0.691 AC: 1006725 AN: 1456486 Hom.: 350762 Cov.: 71 AF XY: 0.693 AC XY: 501740 AN XY: 723992

Gnomad4 AFR exome AF: 0.671

Gnomad4 AMR exome AF: 0.775

Gnomad4 ASJ exome AF: 0.784

Gnomad4 EAS exome AF: 0.959

Gnomad4 SAS exome AF: 0.763

Gnomad4 FIN exome AF: 0.606

Gnomad4 NFE exome AF: 0.674

Gnomad4 OTH exome AF: 0.709

GnomAD4 genome AF: 0.690 AC: 104991 AN: 152214 Hom.: 36573 Cov.: 35 AF XY: 0.691 AC XY: 51381 AN XY: 74398

Gnomad4 AFR AF: 0.671

Gnomad4 AMR AF: 0.745

Gnomad4 ASJ AF: 0.780

Gnomad4 EAS AF: 0.936

Gnomad4 SAS AF: 0.773

Gnomad4 FIN AF: 0.597

Gnomad4 NFE AF: 0.675

Gnomad4 OTH AF: 0.707

Alfa AF: 0.689 Hom.: 11659

Bravo AF: 0.699

Asia WGS AF: 0.841 AC: 2924 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

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	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 28, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Eurofins Ntd Llc (ga)	Oct 17, 2014	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

WFS1-Related Spectrum Disorders Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Wolfram syndrome 1 Benign:1

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. rs1801213 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained. -

Autosomal dominant nonsyndromic hearing loss 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.7
DANN	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1801213; hg19: chr4-6293696;