4-6301520-C-T

Variant names:

• chr4-6301520-C-T
• rs2230719
• NM_006005.3:c.1725C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_006005.3(WFS1):​c.1725C>T​(p.Ala575Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0703 in 1,613,824 control chromosomes in the GnomAD database, including 4,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (419 hom., cov: 34)
  • Exomes 𝑓: 0.071 (4025 hom.)
• Consequence: WFS1 NM_006005.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.518

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]

ENSG00000286176 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 4-6301520-C-T is Benign according to our data. Variant chr4-6301520-C-T is described in ClinVar as [Benign]. Clinvar id is 45438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6301520-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.518 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0717 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3	c.1725C>T	p.Ala575Ala	synonymous_variant	Exon 8 of 8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.1725C>T	p.Ala575Ala	synonymous_variant	Exon 8 of 8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.1725C>T	p.Ala575Ala	synonymous_variant	Exon 8 of 8	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes AF: 0.0661 AC: 10068 AN: 152206 Hom.: 420 Cov.: 34

Gnomad AFR AF: 0.0735

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.0514

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.0623

Gnomad FIN AF: 0.0238

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0734

Gnomad OTH AF: 0.0626

GnomAD3 exomes AF: 0.0573 AC: 14395 AN: 251166 Hom.: 498 AF XY: 0.0585 AC XY: 7946 AN XY: 135840

Gnomad AFR exome AF: 0.0739

Gnomad AMR exome AF: 0.0339

Gnomad ASJ exome AF: 0.0914

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0600

Gnomad FIN exome AF: 0.0283

Gnomad NFE exome AF: 0.0729

Gnomad OTH exome AF: 0.0606

GnomAD4 exome AF: 0.0708 AC: 103422 AN: 1461500 Hom.: 4025 Cov.: 102 AF XY: 0.0705 AC XY: 51292 AN XY: 727098

Gnomad4 AFR exome AF: 0.0741

Gnomad4 AMR exome AF: 0.0356

Gnomad4 ASJ exome AF: 0.0914

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0617

Gnomad4 FIN exome AF: 0.0295

Gnomad4 NFE exome AF: 0.0767

Gnomad4 OTH exome AF: 0.0671

GnomAD4 genome AF: 0.0661 AC: 10066 AN: 152324 Hom.: 419 Cov.: 34 AF XY: 0.0636 AC XY: 4738 AN XY: 74476

Gnomad4 AFR AF: 0.0732

Gnomad4 AMR AF: 0.0513

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.0628

Gnomad4 FIN AF: 0.0238

Gnomad4 NFE AF: 0.0734

Gnomad4 OTH AF: 0.0619

Alfa AF: 0.0681 Hom.: 466

Bravo AF: 0.0685

Asia WGS AF: 0.0280 AC: 96 AN: 3478

EpiCase AF: 0.0770

EpiControl AF: 0.0766

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Nov 20, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ala575Ala in Exon 08 of WFS1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 7.3% (274/3738) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2230719). -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 22, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

WFS1-Related Spectrum Disorders Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Autosomal dominant nonsyndromic hearing loss 6 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.38
CADD	Benign	3.2
DANN	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2230719; hg19: chr4-6303247; COSMIC: COSV56990625; COSMIC: COSV56990625;