4-6302311-T-C

Variant names:

• chr4-6302311-T-C
• rs761114952
• NM_006005.3:c.2516T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4 BP6

The NM_006005.3(WFS1):​c.2516T>C​(p.Val839Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,458,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.94
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 23 uncertain in NM_006005.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.34387016).
• BP6: Variant 4-6302311-T-C is Benign according to our data. Variant chr4-6302311-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 505203.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3	c.2516T>C	p.Val839Ala	missense_variant	Exon 8 of 8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.2516T>C	p.Val839Ala	missense_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.2516T>C	p.Val839Ala	missense_variant	Exon 8 of 8	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 248476 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1458878 Hom.: 0 Cov.: 99 AF XY: 0.00000138 AC XY: 1 AN XY: 725560

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.0000671 AC: 3 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110986

Other (OTH) AF: 0.0000166 AC: 1 AN: 60282

GnomAD4 genome Cov.: 35

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 839 of the WFS1 protein (p.Val839Ala). This variant is present in population databases (rs761114952, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with WFS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 505203). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt WFS1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jan 09, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Uncertain:1

Jun 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val839Ala variant in WFS1 has not been previously reported in individuals with hearing loss, but has been identified in 1/8552 East Asian chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs7 61114952). Although this variant has been seen in the general population, its fr equency is not high enough to rule out a pathogenic role. Computational predicti on tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenic ity. In summary, the clinical significance of the p.Val839Ala variant is uncerta in. -

Wolfram syndrome 1 Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. However no sufficient evidence is found to ascertain the role of this particular variant rs761114952 in Wolfram's syndrome yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	21
DANN	Benign	0.71
DEOGEN2	Benign	0.15	T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.031
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.85	.;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Uncertain	-0.0074	T
MutationAssessor	Benign	1.9	L;L
PhyloP100		2.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.79	N;N
REVEL	Uncertain	0.45
Sift	Benign	0.47	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.41	B;B
Vest4		0.45
MutPred		0.31		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);
MVP		0.99
ClinPred		0.097	T
GERP RS		4.8
Varity_R		0.093
gMVP		0.83
Mutation Taster		=53/47	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: rs761114952; hg19: chr4-6304038;