rs28937893

chr4-6301941-G-Achr4-6301941-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_006005.3(WFS1):c.2146G>A(p.Ala716Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A716A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.58

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 Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in NM_006005.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921
• PP5: Variant 4-6301941-G-A is Pathogenic according to our data. Variant chr4-6301941-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6301941-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3	c.2146G>A	p.Ala716Thr	missense_variant	8/8	ENST00000226760.5
WFS1	NM_001145853.1	c.2146G>A	p.Ala716Thr	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.2146G>A	p.Ala716Thr	missense_variant	8/8	1	NM_006005.3	P2
	ENST00000661896.1	n.1337+1974C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000804 AC: 2 AN: 248846 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135078

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460508 Hom.: 0 Cov.: 99 AF XY: 0.00000413 AC XY: 3 AN XY: 726570

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2023	For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on WFS1 protein function. ClinVar contains an entry for this variant (Variation ID: 4520). This missense change has been observed in individual(s) with autosomal dominant nonsyndromic deafness (PMID: 11709537, 11709538; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs28937893, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 716 of the WFS1 protein (p.Ala716Thr). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11709537, 11709538, 17492394, 12490066, 12707188, 28432734, 29529044, 29277467, 36208030, 36225977, 34599366, 36098976) -

Autosomal dominant nonsyndromic hearing loss 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2007

- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 16, 2016

The p.Ala716Thr variant in WFS1 has been reported in six families with low frequ ency sensorineural hearing loss and was shown to segregate in >30 affected famil y members (Bespalova 2001, Young 2001, Fukuoka 2007, LMM Data). All individuals heterozygous for the p.Ala716Thr variant were reported to have only hearing loss , and one individual homozygous for the variant had clinical features of Wolfram syndrome (Young 2001). This variant has been identified in 1/30736 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinsti tute.org/; dbSNP rs28937893). In summary, this variant meets criteria to be clas sified as pathogenic for autosomal dominant hearing loss; however, its clinical significance for autosomal recessive Wolfram syndrome is uncertain. ACMG/AMP Cri teria applied: PP1_Strong; PM2; PS4_Moderate; PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.5	N;N
REVEL	Pathogenic	0.80
Sift	Benign	0.12	T;T
Sift4G	Benign	0.11	T;T
Polyphen		1.0	D;D
Vest4		0.83
MutPred		0.70		Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);
MVP		1.0
ClinPred		0.78	D
GERP RS		5.5
Varity_R		0.11
gMVP		0.70

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: rs28937893; hg19: chr4-6303668; COSMIC: COSV105051932; COSMIC: COSV105051932;