rs141225426

chr4-6289021-C-Gchr4-6289021-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006005.3(WFS1):c.350C>G(p.Thr117Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,607,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T117M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0750

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06623882).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3	c.350C>G	p.Thr117Arg	missense_variant	4/8	ENST00000226760.5
WFS1	NM_001145853.1	c.350C>G	p.Thr117Arg	missense_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.350C>G	p.Thr117Arg	missense_variant	4/8	1	NM_006005.3	P2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000212 AC: 5 AN: 236282 Hom.: 0 AF XY: 0.0000235 AC XY: 3 AN XY: 127854

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: 0.00

Gnomad FIN exome AF: 0.000101

Gnomad NFE exome AF: 0.0000283

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1455696 Hom.: 0 Cov.: 32 AF XY: 0.00000415 AC XY: 3 AN XY: 723300

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: 0.00

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.00000631

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152174 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000274 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000330 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	0.21
Dann	Benign	0.43
DEOGEN2	Benign	0.075	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.030	N
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.066	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.97	N;N
REVEL	Benign	0.21
Sift	Benign	0.51	T;T
Sift4G	Benign	0.49	T;T
Polyphen		0.0020	B;B
Vest4		0.27
MutPred		0.24		Gain of solvent accessibility (P = 0.0917);Gain of solvent accessibility (P = 0.0917);
MVP		0.51
ClinPred		0.013	T
GERP RS		-0.86
Varity_R		0.033
gMVP		0.28

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: rs141225426; hg19: chr4-6290748;