NM_006005.3:c.2565A>G

Variant names:

• chr4-6302360-A-G
• rs1046316
• NM_006005.3:c.2565A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006005.3(WFS1):​c.2565A>G​(p.Ser855Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.699 in 1,612,712 control chromosomes in the GnomAD database, including 397,452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S855S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.72 (39478 hom., cov: 36)
  • Exomes 𝑓: 0.70 (357974 hom.)
• Consequence: WFS1 NM_006005.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -2.52
• Publications: 43 publications found

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 Gene-Disease associations (from GenCC):

• Wolfram-like syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, ClinGen, Orphanet
• Wolfram syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• autosomal dominant nonsyndromic hearing loss 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cataract 41

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Wolfram syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• type 2 diabetes mellitus

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000286176 (HGNC:58722):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 4-6302360-A-G is Benign according to our data. Variant chr4-6302360-A-G is described in ClinVar as Benign. ClinVar VariationId is 45456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.913 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006005.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFS1	NM_006005.3	MANE Select	c.2565A>G	p.Ser855Ser	synonymous	Exon 8 of 8	NP_005996.2
	WFS1	NM_001145853.1		c.2565A>G	p.Ser855Ser	synonymous	Exon 8 of 8	NP_001139325.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFS1	ENST00000226760.5	TSL:1 MANE Select	c.2565A>G	p.Ser855Ser	synonymous	Exon 8 of 8	ENSP00000226760.1
	WFS1	ENST00000503569.5	TSL:1	c.2565A>G	p.Ser855Ser	synonymous	Exon 8 of 8	ENSP00000423337.1
	WFS1	ENST00000673991.1		c.2601A>G	p.Ser867Ser	synonymous	Exon 8 of 8	ENSP00000501033.1

Frequencies

GnomAD3 genomes AF: 0.716 AC: 108980 AN: 152142 Hom.: 39427 Cov.: 36

Gnomad AFR AF: 0.758

Gnomad AMI AF: 0.568

Gnomad AMR AF: 0.756

Gnomad ASJ AF: 0.784

Gnomad EAS AF: 0.934

Gnomad SAS AF: 0.774

Gnomad FIN AF: 0.595

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.678

Gnomad OTH AF: 0.725

GnomAD2 exomes AF: 0.725 AC: 181149 AN: 249728 AF XY: 0.724

Gnomad AFR exome AF: 0.761

Gnomad AMR exome AF: 0.788

Gnomad ASJ exome AF: 0.789

Gnomad EAS exome AF: 0.932

Gnomad FIN exome AF: 0.603

Gnomad NFE exome AF: 0.675

Gnomad OTH exome AF: 0.718

GnomAD4 exome AF: 0.697 AC: 1018455 AN: 1460452 Hom.: 357974 Cov.: 100 AF XY: 0.699 AC XY: 507815 AN XY: 726564

African (AFR) AF: 0.764 AC: 25569 AN: 33474

American (AMR) AF: 0.784 AC: 35024 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.788 AC: 20586 AN: 26122

East Asian (EAS) AF: 0.958 AC: 38035 AN: 39700

South Asian (SAS) AF: 0.764 AC: 65909 AN: 86244

European-Finnish (FIN) AF: 0.605 AC: 31586 AN: 52188

Middle Eastern (MID) AF: 0.757 AC: 4367 AN: 5768

European-Non Finnish (NFE) AF: 0.678 AC: 753963 AN: 1111890

Other (OTH) AF: 0.719 AC: 43416 AN: 60370

GnomAD4 genome AF: 0.716 AC: 109089 AN: 152260 Hom.: 39478 Cov.: 36 AF XY: 0.715 AC XY: 53236 AN XY: 74446

African (AFR) AF: 0.758 AC: 31500 AN: 41566

American (AMR) AF: 0.756 AC: 11572 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 2721 AN: 3470

East Asian (EAS) AF: 0.935 AC: 4844 AN: 5182

South Asian (SAS) AF: 0.774 AC: 3735 AN: 4824

European-Finnish (FIN) AF: 0.595 AC: 6301 AN: 10598

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.678 AC: 46131 AN: 68004

Other (OTH) AF: 0.727 AC: 1539 AN: 2116

Alfa AF: 0.684 Hom.: 9056

Bravo AF: 0.731

EpiCase AF: 0.686

EpiControl AF: 0.692

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 30, 2013

Eurofins Ntd Llc (ga)

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

Feb 28, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 12107816)

WFS1-Related Spectrum Disorders Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Autosomal dominant nonsyndromic hearing loss 6 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.049
DANN	Benign	0.33
PhyloP100		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1046316; hg19: chr4-6304087; COSMIC: COSV56990634; COSMIC: COSV56990634;