4-6302365-C-G

Variant names:

• chr4-6302365-C-G
• rs573202595
• NM_006005.3:c.2570C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_006005.3(WFS1):​c.2570C>G​(p.Thr857Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T857I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.37

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]

ENSG00000286176 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 14 uncertain in NM_006005.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09295532).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3	c.2570C>G	p.Thr857Ser	missense_variant	Exon 8 of 8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.2570C>G	p.Thr857Ser	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.2570C>G	p.Thr857Ser	missense_variant	Exon 8 of 8	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460712 Hom.: 0 Cov.: 87 AF XY: 0.00 AC XY: 0 AN XY: 726700

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 35

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 857 of the WFS1 protein (p.Thr857Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with WFS1-related conditions. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	0.0099	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	12
DANN	Benign	0.60
DEOGEN2	Benign	0.068	T;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.35	.;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.093	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-0.81	N;N
PhyloP100		3.4
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.13	N;N
REVEL	Benign	0.24
Sift	Benign	0.57	T;T
Sift4G	Benign	0.60	T;T
Polyphen		0.0010	B;B
Vest4		0.070
MutPred		0.23		Gain of disorder (P = 0.0272);Gain of disorder (P = 0.0272);
MVP		0.76
ClinPred		0.14	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.050
gMVP		0.56
Mutation Taster		=86/14	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

Publications

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Other links and lift over

dbSNP: rs573202595; hg19: chr4-6304092;