4-6301587-G-C

Variant names:

• chr4-6301587-G-C
• rs140125843
• NM_006005.3:c.1792G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006005.3(WFS1):​c.1792G>C​(p.Ala598Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 34)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.251

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23115003).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3	c.1792G>C	p.Ala598Pro	missense_variant	Exon 8 of 8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.1792G>C	p.Ala598Pro	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.1792G>C	p.Ala598Pro	missense_variant	Exon 8 of 8	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152212 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 99

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152212 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74360

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	9.7
DANN	Uncertain	0.97
DEOGEN2	Benign	0.098	T;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.90	.;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.1	N;N
REVEL	Pathogenic	0.67
Sift	Benign	0.079	T;T
Sift4G	Uncertain	0.039	D;D
Polyphen		0.052	B;B
Vest4		0.38
MutPred		0.43		Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);
MVP		0.99
ClinPred		0.090	T
GERP RS		-2.6
Varity_R		0.16
gMVP		0.90

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: rs140125843; hg19: chr4-6303314;