4-6300818-C-T

Variant names:

• chr4-6300818-C-T
• rs56072215
• NM_006005.3:c.1023C>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.1023C>T​(p.Phe341Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0684 in 1,613,996 control chromosomes in the GnomAD database, including 4,378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (303 hom., cov: 32)
  • Exomes 𝑓: 0.070 (4075 hom.)
• Consequence: WFS1 NM_006005.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.550

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 4-6300818-C-T is Benign according to our data. Variant chr4-6300818-C-T is described in ClinVar as [Benign]. Clinvar id is 45428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6300818-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.55 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3	c.1023C>T	p.Phe341Phe	synonymous_variant	Exon 8 of 8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.1023C>T	p.Phe341Phe	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.1023C>T	p.Phe341Phe	synonymous_variant	Exon 8 of 8	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes AF: 0.0498 AC: 7581 AN: 152108 Hom.: 304 Cov.: 32

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.0484

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0631

Gnomad FIN AF: 0.0236

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0743

Gnomad OTH AF: 0.0537

GnomAD3 exomes AF: 0.0542 AC: 13625 AN: 251454 Hom.: 482 AF XY: 0.0568 AC XY: 7719 AN XY: 135898

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.0336

Gnomad ASJ exome AF: 0.0937

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.0615

Gnomad FIN exome AF: 0.0284

Gnomad NFE exome AF: 0.0742

Gnomad OTH exome AF: 0.0624

GnomAD4 exome AF: 0.0703 AC: 102751 AN: 1461770 Hom.: 4075 Cov.: 96 AF XY: 0.0704 AC XY: 51173 AN XY: 727190

Gnomad4 AFR exome AF: 0.0129

Gnomad4 AMR exome AF: 0.0349

Gnomad4 ASJ exome AF: 0.0938

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.0629

Gnomad4 FIN exome AF: 0.0296

Gnomad4 NFE exome AF: 0.0779

Gnomad4 OTH exome AF: 0.0650

GnomAD4 genome AF: 0.0498 AC: 7581 AN: 152226 Hom.: 303 Cov.: 32 AF XY: 0.0472 AC XY: 3512 AN XY: 74412

Gnomad4 AFR AF: 0.0135

Gnomad4 AMR AF: 0.0482

Gnomad4 ASJ AF: 0.103

Gnomad4 EAS AF: 0.00136

Gnomad4 SAS AF: 0.0634

Gnomad4 FIN AF: 0.0236

Gnomad4 NFE AF: 0.0743

Gnomad4 OTH AF: 0.0531

Alfa AF: 0.0672 Hom.: 218

Bravo AF: 0.0507

Asia WGS AF: 0.0230 AC: 78 AN: 3476

EpiCase AF: 0.0792

EpiControl AF: 0.0785

ClinVar

Significance: Benign

Submissions summary: Benign:10

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

- -

Mar 05, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

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

Phe341Phe 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 7.1% (496/7020) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs56072215). -

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. -

Wolfram syndrome 1 Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. rs56072215 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	4.1
DANN	Benign	0.74
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: rs56072215; hg19: chr4-6302545; COSMIC: COSV56988143; COSMIC: COSV56988143;