rs150771247

chr4-6291968-G-Achr4-6291968-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_006005.3(WFS1):c.683G>A(p.Arg228His) variant causes a missense change. The variant allele was found at a frequency of 0.00131 in 1,610,506 control chromosomes in the GnomAD database, including 5 homozygotes. 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. R228L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0014 (5 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:8 B:6
• Conservation: PhyloP100: 3.80

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3	c.683G>A	p.Arg228His	missense_variant	6/8	ENST00000226760.5
WFS1	NM_001145853.1	c.683G>A	p.Arg228His	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.683G>A	p.Arg228His	missense_variant	6/8	1	NM_006005.3	P2

Frequencies

GnomAD3 genomes AF: 0.000854 AC: 130 AN: 152254 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000759 AC: 184 AN: 242304 Hom.: 1 AF XY: 0.000714 AC XY: 94 AN XY: 131604

Gnomad AFR exome AF: 0.000459

Gnomad AMR exome AF: 0.0000588

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000553

Gnomad SAS exome AF: 0.0000678

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00153

Gnomad OTH exome AF: 0.000847

GnomAD4 exome AF: 0.00136 AC: 1980 AN: 1458134 Hom.: 5 Cov.: 31 AF XY: 0.00131 AC XY: 953 AN XY: 725056

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000113

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.0000383

Gnomad4 NFE exome AF: 0.00170

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.000847 AC: 129 AN: 152372 Hom.: 0 Cov.: 34 AF XY: 0.000725 AC XY: 54 AN XY: 74514

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00152 Hom.: 0

Bravo AF: 0.000858

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000785 AC: 95

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:8 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2021	This variant is associated with the following publications: (PMID: 25133958, 33112832, 18544103) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	WFS1: PM2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 20, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2019	The WFS1 p.Arg228His variant (rs150771247) has been reported in one individual with a diagnosis of cerebellar ataxia who also harbored two high frequency WFS1 variants on the other allele (Fogel 2014). The p.Arg228His variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.15% in the non-Finnish European population (identified in 181 out of 122,852 chromosomes with 1 homozygote), and is classified as a variant of uncertain significance in ClinVar (Variant ID: 198190). The arginine at codon 228 is moderately conserved considering 12 species (Alamut software v2.10.0), and computational analyses predict that this variant does affect the structure/function of the WFS1 protein (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). However, based on the available information, the clinical significance of the WFS1 variant cannot be determined with certainty. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 07, 2022	DNA sequence analysis of the WFS1 gene demonstrated a sequence change, c.683G>A, in exon 6 that results in an amino acid change, p.Arg228His. This sequence change has been described in the gnomAD database with a frequency of 0.15% in the European subpopulation, including one homozygous individual (dbSNP rs150771247). The p.Arg228His change affects a moderately conserved amino acid residue located in a domain of the WFS1 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg228His substitution. The p.Arg228His change as been reported in one individual with dementia, optic atrophy and sensorineural hearing loss. However, a second clearly pathogenic variant in the WFS1 gene was not identified (PMID: 25133958). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg228His change remains unknown at this time. Biallelic pathogenic variants in WFS1 have been associated with autosomal recessive Wolfram syndrome, which is characterized by diabetes insipidus, diabetes mellitus, optic atrophy and deafness (OMIM# 222300). Heterozygous pathogenic variants in WFS1 have also been associated with autosomal dominant Wolfram-like syndrome (OMIM# 614296) and sensorineural hearing loss (OMIM# 600965). -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 23, 2024	Variant summary: WFS1 c.683G>A (p.Arg228His) results in a non-conservative amino acid change located in the Wolframin, EF-hand domain (IPR045460) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 1610506 control chromosomes, predominantly at a frequency of 0.0017 within the Non-Finnish European subpopulation in the gnomAD database, including 4 homozygotes (gnomAD v4). c.683G>A has been reported as a single heterozygous variant in one individual with early onset dementia, optic atrophy, and sensorineural hearing loss, and was at a compound heterozygous along with a second pathogenic variant in an individual with recessive WFS1-related disorders (example, Astuti_2017, Fogel_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Wolfram Syndrome 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28432734, 25133958). ClinVar contains an entry for this variant (Variation ID: 198190). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 06, 2017	Variant classified as Uncertain Significance - Favor Benign. The p.Arg228His var iant in WFS1 has been previously identified in 1 individual with hearing loss an d hypothyroidism (LMM unpublished data) and 1 individual with cerebellar ataxia who also had some clinical features associated with Wolfram syndrome (Fogel 2014 ). Neither individual carried a second, clinically significant variant in the WF S1 gene (while the proband reported by Fogel et al had two additional WFS1 varia nts, our laboratory classifies these variants as benign based on high frequency in the African American population). The p.Arg228His variant has also been ident ified in 0.15% (181/122852) of European chromosomes, including 1 homozygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs150771247). Computational prediction tools and conservation analyses do not p rovide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Arg228His variant is uncertain, its frequenc y in the general population and identification in the homozygous state in 1 indi vidual from the general population suggests that it is more likely to be benign. -

Wolfram-like syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2008

- -

WFS1-Related Spectrum Disorders Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

WFS1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 05, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal dominant nonsyndromic hearing loss 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.32	T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.92	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.63
Sift	Benign	0.037	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;D
Vest4		0.87
MVP		1.0
ClinPred		0.066	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.14
gMVP		0.61

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: rs150771247; hg19: chr4-6293695; COSMIC: COSV99901090; COSMIC: COSV99901090;