4-6301953-A-G

Variant names:

• chr4-6301953-A-G
• rs1805070
• NM_006005.3:c.2158A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_006005.3(WFS1):​c.2158A>G​(p.Ile720Val) variant causes a missense change. The variant allele was found at a frequency of 0.00368 in 1,612,836 control chromosomes in the GnomAD database, including 149 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I720M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0045 (15 hom., cov: 34)
  • Exomes 𝑓: 0.0036 (134 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.91
• Publications: 28 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 -18 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 21 uncertain in NM_006005.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0034231544).
• BP6: Variant 4-6301953-A-G is Benign according to our data. Variant chr4-6301953-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0585 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.2158A>G	p.Ile720Val	missense	Exon 8 of 8	NP_005996.2
	WFS1	NM_001145853.1		c.2158A>G	p.Ile720Val	missense	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.2158A>G	p.Ile720Val	missense	Exon 8 of 8	ENSP00000226760.1
	WFS1	ENST00000503569.5	TSL:1	c.2158A>G	p.Ile720Val	missense	Exon 8 of 8	ENSP00000423337.1
	WFS1	ENST00000673991.1		c.2194A>G	p.Ile732Val	missense	Exon 8 of 8	ENSP00000501033.1

Frequencies

GnomAD3 genomes AF: 0.00448 AC: 682 AN: 152216 Hom.: 15 Cov.: 34

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0642

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0203

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00734 AC: 1828 AN: 248996 AF XY: 0.00712

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.000901

Gnomad EAS exome AF: 0.0572

Gnomad FIN exome AF: 0.0220

Gnomad NFE exome AF: 0.00138

Gnomad OTH exome AF: 0.00837

GnomAD4 exome AF: 0.00360 AC: 5251 AN: 1460502 Hom.: 134 Cov.: 99 AF XY: 0.00357 AC XY: 2596 AN XY: 726548

African (AFR) AF: 0.0000896 AC: 3 AN: 33474

American (AMR) AF: 0.000134 AC: 6 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 29 AN: 26120

East Asian (EAS) AF: 0.0698 AC: 2769 AN: 39692

South Asian (SAS) AF: 0.00267 AC: 230 AN: 86242

European-Finnish (FIN) AF: 0.0224 AC: 1169 AN: 52222

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.000611 AC: 679 AN: 1111918

Other (OTH) AF: 0.00596 AC: 360 AN: 60372

GnomAD4 genome AF: 0.00448 AC: 683 AN: 152334 Hom.: 15 Cov.: 34 AF XY: 0.00585 AC XY: 436 AN XY: 74492

African (AFR) AF: 0.0000962 AC: 4 AN: 41586

American (AMR) AF: 0.000327 AC: 5 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.0642 AC: 332 AN: 5172

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4830

European-Finnish (FIN) AF: 0.0203 AC: 216 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00134 AC: 91 AN: 68024

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00273 Hom.: 20

Bravo AF: 0.00325

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00721 AC: 875

Asia WGS AF: 0.0330 AC: 113 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ile720Val in Exon 08 of WFS1: This variant is not expected to have clinical sign ificance because it has been identified in 12.2% (11/90) of chromosomes from a p opulation in the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP; rs180 5070).

Jun 09, 2014

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.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 24, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Feb 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

WFS1-Related Spectrum Disorders Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Type 2 diabetes mellitus;C1833021:Autosomal dominant nonsyndromic hearing loss 6;C3280358:Wolfram-like syndrome;C3805412:Cataract 41;C4551693:Wolfram syndrome 1 Benign:1

Nov 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diabetes mellitus Benign:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

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. Though rs1805070 is prevalent in Type I Diabetes Mellitus cases, more evidence is required to ascertain the significance.

Monogenic diabetes Benign:1

Jan 25, 2019

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

ACMG criteria: BA1 (5.7% in gnomAD East Asian, 2.1% in EurF), BS2 (32 homozygotes in gnomAD)=benign (REVEL 0.433 + PP3/3 predictors + BP4/7 predictors= conflicting evidence, not using)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.9
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.57	N
REVEL	Uncertain	0.43
Sift	Benign	0.20	T
Sift4G	Benign	0.22	T
Polyphen		0.0040	B
Vest4		0.19
MVP		0.93
ClinPred		0.014	T
GERP RS		0.34
Varity_R		0.035
gMVP		0.58
Mutation Taster		=84/16	polymorphism

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: rs1805070; hg19: chr4-6303680; COSMIC: COSV56990282; COSMIC: COSV56990282;