chr4-6295182-G-C

Variant names:

• chr4-6295182-G-C
• rs61735404
• NM_006005.3:c.854G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_006005.3(WFS1):​c.854G>C​(p.Arg285Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R285C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.28

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 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_006005.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3	c.854G>C	p.Arg285Pro	missense_variant	Exon 7 of 8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.854G>C	p.Arg285Pro	missense_variant	Exon 7 of 8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.854G>C	p.Arg285Pro	missense_variant	Exon 7 of 8	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249786 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135470

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-0.032
Eigen_PC	Benign	-0.0023
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.85	.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.0	M;M
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.8	N;N
REVEL	Pathogenic	0.69
Sift	Benign	0.16	T;T
Sift4G	Uncertain	0.023	D;D
Polyphen		0.63	P;P
Vest4		0.80
MutPred		0.41		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);
MVP		1.0
ClinPred		0.79	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.86

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: rs61735404; hg19: chr4-6296909;