4-6293966-C-G

Variant names:

• chr4-6293966-C-G
• rs6446482
• NM_006005.3:c.713-1075C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006005.3(WFS1):​c.713-1075C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 152,072 control chromosomes in the GnomAD database, including 31,031 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.63 (31031 hom., cov: 33)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:7
• Conservation: PhyloP100: 1.04
• Publications: 33 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-6293966-C-G is Benign according to our data. Variant chr4-6293966-C-G is described in ClinVar as Benign. ClinVar VariationId is 4528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.91 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.713-1075C>G		intron	N/A	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.713-1075C>G		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.713-1075C>G		intron	N/A	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.713-1075C>G		intron	N/A	ENSP00000423337.1	O76024
	WFS1	ENST00000852027.1		c.806-1075C>G		intron	N/A	ENSP00000522086.1

Frequencies

GnomAD3 genomes AF: 0.632 AC: 96092 AN: 151954 Hom.: 30991 Cov.: 33

Gnomad AFR AF: 0.645

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.693

Gnomad ASJ AF: 0.671

Gnomad EAS AF: 0.932

Gnomad SAS AF: 0.703

Gnomad FIN AF: 0.566

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.594

Gnomad OTH AF: 0.650

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

GnomAD4 genome AF: 0.632 AC: 96182 AN: 152072 Hom.: 31031 Cov.: 33 AF XY: 0.635 AC XY: 47204 AN XY: 74320

African (AFR) AF: 0.645 AC: 26710 AN: 41436

American (AMR) AF: 0.694 AC: 10612 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.671 AC: 2331 AN: 3472

East Asian (EAS) AF: 0.932 AC: 4817 AN: 5166

South Asian (SAS) AF: 0.702 AC: 3380 AN: 4812

European-Finnish (FIN) AF: 0.566 AC: 5998 AN: 10588

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.594 AC: 40416 AN: 67990

Other (OTH) AF: 0.653 AC: 1380 AN: 2114

Alfa AF: 0.612 Hom.: 3548

Bravo AF: 0.642

Asia WGS AF: 0.812 AC: 2824 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Wolfram syndrome 1 (2)
-	-	1	Diabetes mellitus, noninsulin-dependent, association with (1)
-	-	1	not specified (1)
1	-	-	Type 2 diabetes mellitus (1)
-	-	1	Wolfram syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.9
DANN	Benign	0.70
PhyloP100		1.0
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: rs6446482; hg19: chr4-6295693;