4-6291968-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_006005.3(WFS1):c.683G>T(p.Arg228Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,458,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R228H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.80

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-6291968-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3	c.683G>T	p.Arg228Leu	missense_variant	6/8	ENST00000226760.5
WFS1	NM_001145853.1	c.683G>T	p.Arg228Leu	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.683G>T	p.Arg228Leu	missense_variant	6/8	1	NM_006005.3	P2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000825 AC: 2 AN: 242304 Hom.: 0 AF XY: 0.00000760 AC XY: 1 AN XY: 131604

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: 0.00

Gnomad NFE exome AF: 0.00000914

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1458134 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725056

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: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.76	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.0	N;N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.70	P;P
Vest4		0.73
MutPred		0.35		Loss of MoRF binding (P = 0.0034);Loss of MoRF binding (P = 0.0034);
MVP		1.0
ClinPred		0.71	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.26
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150771247; hg19: chr4-6293695;