rs71530925

Positions:

• chr4-6301177-C-G
• chr4-6301177-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP5

The NM_006005.3(WFS1):​c.1382C>G​(p.Thr461Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in Lovd as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T461P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.75

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-6301176-A-C is described in Lovd as [Pathogenic].
• PP5: Variant 4-6301177-C-G is Pathogenic according to our data. Variant chr4-6301177-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.1382C>G	p.Thr461Ser	missense_variant	8/8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.1382C>G	p.Thr461Ser	missense_variant	8/8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.1382C>G	p.Thr461Ser	missense_variant	8/8	1	NM_006005.3	ENSP00000226760	P2
	ENST00000661896.1	n.1337+2738G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 101

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.012
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.74	.;T
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.50	D;D
MetaSVM	Uncertain	-0.018	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	0.66	N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.38
Sift	Benign	0.097	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.037	B;B
Vest4		0.54
MutPred		0.24		Loss of glycosylation at T461 (P = 0.0702);Loss of glycosylation at T461 (P = 0.0702);
MVP		0.98
ClinPred		0.40	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.69

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: rs71530925; hg19: chr4-6302904;