4-6298213-C-T

Variant names:

• chr4-6298213-C-T
• rs3821943
• NM_006005.3:c.862-2444C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006005.3(WFS1):​c.862-2444C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 152,146 control chromosomes in the GnomAD database, including 20,616 homozygotes. 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 0.51 (20616 hom., cov: 35)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.76
• Publications: 19 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):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Wolfram-like syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.805 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006005.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFS1	NM_006005.3	MANE Select	c.862-2444C>T		intron	N/A	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.862-2444C>T		intron	N/A	NP_001139325.1	O76024

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFS1	ENST00000226760.5	TSL:1 MANE Select	c.862-2444C>T		intron	N/A	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.862-2444C>T		intron	N/A	ENSP00000423337.1	O76024
	WFS1	ENST00000852027.1		c.955-2444C>T		intron	N/A	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.508 AC: 77278 AN: 152028 Hom.: 20602 Cov.: 35

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.825

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.494

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.541

Gnomad OTH AF: 0.542

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.508 AC: 77306 AN: 152146 Hom.: 20616 Cov.: 35 AF XY: 0.509 AC XY: 37868 AN XY: 74380

African (AFR) AF: 0.372 AC: 15420 AN: 41504

American (AMR) AF: 0.593 AC: 9069 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 2133 AN: 3466

East Asian (EAS) AF: 0.825 AC: 4266 AN: 5168

South Asian (SAS) AF: 0.579 AC: 2791 AN: 4818

European-Finnish (FIN) AF: 0.494 AC: 5229 AN: 10588

Middle Eastern (MID) AF: 0.500 AC: 146 AN: 292

European-Non Finnish (NFE) AF: 0.541 AC: 36772 AN: 67990

Other (OTH) AF: 0.543 AC: 1149 AN: 2116

Alfa AF: 0.530 Hom.: 48635

Bravo AF: 0.510

Asia WGS AF: 0.656 AC: 2284 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.18
DANN	Benign	0.63
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs3821943; hg19: chr4-6299940;