4-6301587-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000226760.5(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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A598T) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 34)
• Consequence: WFS1 ENST00000226760.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.251
• Publications: 4 publications found

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]

WFS1 Gene-Disease associations (from GenCC):

• Wolfram-like syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, ClinGen, Orphanet
• Wolfram syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• autosomal dominant nonsyndromic hearing loss 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cataract 41

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Wolfram syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• type 2 diabetes mellitus

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000286176 (HGNC:58722):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000226760.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFS1	NM_006005.3	MANE Select	c.1792G>C	p.Ala598Pro	missense	Exon 8 of 8	NP_005996.2
	WFS1	NM_001145853.1		c.1792G>C	p.Ala598Pro	missense	Exon 8 of 8	NP_001139325.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFS1	ENST00000226760.5	TSL:1 MANE Select	c.1792G>C	p.Ala598Pro	missense	Exon 8 of 8	ENSP00000226760.1
	WFS1	ENST00000503569.5	TSL:1	c.1792G>C	p.Ala598Pro	missense	Exon 8 of 8	ENSP00000423337.1
	WFS1	ENST00000673991.1		c.1828G>C	p.Ala610Pro	missense	Exon 8 of 8	ENSP00000501033.1

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.25
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.1	N
REVEL	Pathogenic	0.67
Sift	Benign	0.079	T
Sift4G	Uncertain	0.039	D
Polyphen		0.052	B
Vest4		0.38
MutPred		0.43		Loss of sheet (P = 0.0084)
MVP		0.99
ClinPred		0.090	T
GERP RS		-2.6
Varity_R		0.16
gMVP		0.90
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs140125843; hg19: chr4-6303314;