chr4-6291623-T-C

Variant names:

• chr4-6291623-T-C
• rs10012946
• NM_006005.3:c.631+256T>C

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.631+256T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.64 in 152,098 control chromosomes in the GnomAD database, including 31,772 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.64 (31772 hom., cov: 33)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.42
• Publications: 38 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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 4-6291623-T-C is Benign according to our data. Variant chr4-6291623-T-C is described in ClinVar as Benign. ClinVar VariationId is 684342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.913 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.631+256T>C		intron	N/A	NP_005996.2	O76024
	WFS1	NM_001145853.1		c.631+256T>C		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.631+256T>C		intron	N/A	ENSP00000226760.1	O76024
	WFS1	ENST00000503569.5	TSL:1	c.631+256T>C		intron	N/A	ENSP00000423337.1	O76024
	WFS1	ENST00000684700.1		c.*182T>C		3_prime_UTR	Exon 4 of 4	ENSP00000507806.1	A0A804HK77

Frequencies

GnomAD3 genomes AF: 0.640 AC: 97271 AN: 151980 Hom.: 31730 Cov.: 33

Gnomad AFR AF: 0.655

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.700

Gnomad ASJ AF: 0.678

Gnomad EAS AF: 0.934

Gnomad SAS AF: 0.711

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.601

Gnomad OTH AF: 0.658

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

GnomAD4 genome AF: 0.640 AC: 97365 AN: 152098 Hom.: 31772 Cov.: 33 AF XY: 0.643 AC XY: 47799 AN XY: 74362

African (AFR) AF: 0.655 AC: 27189 AN: 41480

American (AMR) AF: 0.701 AC: 10718 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 2350 AN: 3466

East Asian (EAS) AF: 0.935 AC: 4828 AN: 5162

South Asian (SAS) AF: 0.711 AC: 3428 AN: 4822

European-Finnish (FIN) AF: 0.573 AC: 6075 AN: 10598

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.601 AC: 40835 AN: 67954

Other (OTH) AF: 0.661 AC: 1395 AN: 2110

Alfa AF: 0.624 Hom.: 49694

Bravo AF: 0.651

Asia WGS AF: 0.819 AC: 2848 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.2
DANN	Benign	0.46
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs10012946; hg19: chr4-6293350;