rs4689391

Variant names:

• chr4-6278722-G-A
• rs4689391
• NM_006005.3:c.232+1035G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-6278722-G-A
• chr4-6278722-G-C
• chr4-6278722-G-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.232+1035G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.579 in 152,166 control chromosomes in the GnomAD database, including 26,333 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 0.58 (26333 hom., cov: 34)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.67
• Publications: 17 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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.913 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3	c.232+1035G>A		intron_variant	Intron 2 of 7	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.232+1035G>A		intron_variant	Intron 2 of 7		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.232+1035G>A		intron_variant	Intron 2 of 7	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes AF: 0.579 AC: 88097 AN: 152048 Hom.: 26314 Cov.: 34

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.650

Gnomad EAS AF: 0.934

Gnomad SAS AF: 0.651

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.578

Gnomad OTH AF: 0.604

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

GnomAD4 genome AF: 0.579 AC: 88148 AN: 152166 Hom.: 26333 Cov.: 34 AF XY: 0.581 AC XY: 43221 AN XY: 74382

African (AFR) AF: 0.505 AC: 20966 AN: 41526

American (AMR) AF: 0.658 AC: 10072 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.650 AC: 2256 AN: 3472

East Asian (EAS) AF: 0.935 AC: 4816 AN: 5152

South Asian (SAS) AF: 0.652 AC: 3145 AN: 4822

European-Finnish (FIN) AF: 0.543 AC: 5754 AN: 10600

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.578 AC: 39325 AN: 67980

Other (OTH) AF: 0.606 AC: 1282 AN: 2114

Alfa AF: 0.581 Hom.: 33484

Bravo AF: 0.586

Asia WGS AF: 0.760 AC: 2643 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.25
DANN	Benign	0.50
PhyloP100		-1.7
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: rs4689391; hg19: chr4-6280449;