rs202195756

chr4-6301977-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_006005.3(WFS1):c.2182G>A(p.Gly728Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,612,700 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain risk allele (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G728D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Uncertain significance/Uncertain risk allele criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: 7.58

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 7 uncertain in NM_006005.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3	c.2182G>A	p.Gly728Ser	missense_variant	8/8	ENST00000226760.5
WFS1	NM_001145853.1	c.2182G>A	p.Gly728Ser	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.2182G>A	p.Gly728Ser	missense_variant	8/8	1	NM_006005.3	P2
	ENST00000661896.1	n.1337+1938C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152196 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000404 AC: 10 AN: 247384 Hom.: 0 AF XY: 0.0000669 AC XY: 9 AN XY: 134588

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.000165

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000360

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000199 AC: 29 AN: 1460386 Hom.: 0 Cov.: 98 AF XY: 0.0000220 AC XY: 16 AN XY: 726490

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152314 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74482

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance/Uncertain risk allele

Submissions summary: Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	May 17, 2023	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. 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: 130750). This variant has not been reported in the literature in individuals affected with WFS1-related conditions. This variant is present in population databases (rs202195756, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 728 of the WFS1 protein (p.Gly728Ser). -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 18, 2014	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 05, 2014

The Gly728Ser variant in WFS1 has not been previously reported in individuals wi th hearing loss, but it has been identified in 0.56% (1/178) of Japanese chromos omes by the 1000 Genomes Project (dbSNP rs202195756). Although this variant has been seen in the general population, its frequency is not high enough to rule ou t a pathogenic role. The glycine (Gly) at position 728 is mostly conserved in m ammals and evolutionary distant species; however, one primate (gorilla) carries a serine (Ser) at this position. While this might raise the possibility that a c hange at this position may be tolerated, this occurrence in one species is not s ufficient to make this assumption. Additional computational prediction tools do not provide strong support for or against an impact to the protein. Splicing pre diction tools suggest that this variant may introduce a 3' splice site within th e exon; however, this information is not predictive enough to determine pathogen icity. In summary, the clinical significance of the Gly728Ser variant is uncerta in. -

Wolfram syndrome 1 Other:1

Uncertain risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

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 rs202195756 in Wolfram's syndrome yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Uncertain	0.13
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.9	N;N
REVEL	Pathogenic	0.65
Sift	Benign	0.34	T;T
Sift4G	Uncertain	0.022	D;D
Polyphen		0.96	D;D
Vest4		0.52
MVP		1.0
ClinPred		0.20	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs202195756; hg19: chr4-6303704;