rs1801208

chr4-6301162-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM5 BP4_Strong BP6 BA1

The NM_006005.3(WFS1):c.1367G>A(p.Arg456His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0518 in 1,612,200 control chromosomes in the GnomAD database, including 2,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R456C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.051 (233 hom., cov: 33)
  • Exomes 𝑓: 0.052 (2185 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 9.34

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-6301161-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.005521953).
• BP6: Variant 4-6301162-G-A is Benign according to our data. Variant chr4-6301162-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45434.We mark this variant Likely_benign, oryginal submissions are: {Benign=7, Likely_benign=2, Uncertain_significance=1}. Variant chr4-6301162-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0897 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3	c.1367G>A	p.Arg456His	missense_variant	8/8	ENST00000226760.5
WFS1	NM_001145853.1	c.1367G>A	p.Arg456His	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.1367G>A	p.Arg456His	missense_variant	8/8	1	NM_006005.3	P2
	ENST00000661896.1	n.1337+2753C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0511 AC: 7773 AN: 152054 Hom.: 233 Cov.: 33

Gnomad AFR AF: 0.0367

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.0604

Gnomad ASJ AF: 0.0395

Gnomad EAS AF: 0.0967

Gnomad SAS AF: 0.0633

Gnomad FIN AF: 0.0821

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0493

Gnomad OTH AF: 0.0537

GnomAD3 exomes AF: 0.0567 AC: 14160 AN: 249686 Hom.: 449 AF XY: 0.0577 AC XY: 7796 AN XY: 135076

Gnomad AFR exome AF: 0.0367

Gnomad AMR exome AF: 0.0577

Gnomad ASJ exome AF: 0.0324

Gnomad EAS exome AF: 0.0911

Gnomad SAS exome AF: 0.0646

Gnomad FIN exome AF: 0.0796

Gnomad NFE exome AF: 0.0491

Gnomad OTH exome AF: 0.0650

GnomAD4 exome AF: 0.0519 AC: 75746 AN: 1460028 Hom.: 2185 Cov.: 103 AF XY: 0.0522 AC XY: 37887 AN XY: 726372

Gnomad4 AFR exome AF: 0.0393

Gnomad4 AMR exome AF: 0.0611

Gnomad4 ASJ exome AF: 0.0368

Gnomad4 EAS exome AF: 0.101

Gnomad4 SAS exome AF: 0.0637

Gnomad4 FIN exome AF: 0.0781

Gnomad4 NFE exome AF: 0.0480

Gnomad4 OTH exome AF: 0.0570

GnomAD4 genome AF: 0.0511 AC: 7777 AN: 152172 Hom.: 233 Cov.: 33 AF XY: 0.0526 AC XY: 3916 AN XY: 74394

Gnomad4 AFR AF: 0.0367

Gnomad4 AMR AF: 0.0603

Gnomad4 ASJ AF: 0.0395

Gnomad4 EAS AF: 0.0967

Gnomad4 SAS AF: 0.0635

Gnomad4 FIN AF: 0.0821

Gnomad4 NFE AF: 0.0493

Gnomad4 OTH AF: 0.0546

Alfa AF: 0.0507 Hom.: 393

Bravo AF: 0.0503

TwinsUK AF: 0.0502 AC: 186

ALSPAC AF: 0.0451 AC: 174

ESP6500AA AF: 0.0386 AC: 170

ESP6500EA AF: 0.0508 AC: 437

ExAC AF: 0.0569 AC: 6912

Asia WGS AF: 0.0840 AC: 292 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Arg456His in Exon 08 of WFS1: This variant is not expected to have clinical sign ificance because it has been identified in 5.0% (352/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs1801208). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 02, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 04, 2013	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 26284228, 10679252, 23595122, 25497598) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 02, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Wolfram syndrome 1 Uncertain:1

Uncertain significance, 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. rs1801208 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained. -

WFS1-Related Spectrum Disorders Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Autosomal dominant nonsyndromic hearing loss 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0055	T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.53
Sift	Benign	0.080	T;T
Sift4G	Uncertain	0.011	D;D
Polyphen		1.0	D;D
Vest4		0.31
ClinPred		0.053	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.80

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: rs1801208; hg19: chr4-6302889; COSMIC: COSV56988445; COSMIC: COSV56988445;