4-6289276-C-G

Variant names:

• chr4-6289276-C-G
• rs4689394
• NM_006005.3:c.460+145C>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.460+145C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 1,118,766 control chromosomes in the GnomAD database, including 227,151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32463 hom., cov: 33)
  • Exomes 𝑓: 0.63 (194688 hom.)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.897
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 4-6289276-C-G is Benign according to our data. Variant chr4-6289276-C-G is described in ClinVar as Benign. ClinVar VariationId is 1230484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3	c.460+145C>G		intron_variant	Intron 4 of 7	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.460+145C>G		intron_variant	Intron 4 of 7		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.460+145C>G		intron_variant	Intron 4 of 7	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes AF: 0.646 AC: 98287 AN: 152040 Hom.: 32431 Cov.: 33

Gnomad AFR AF: 0.673

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.702

Gnomad ASJ AF: 0.676

Gnomad EAS AF: 0.942

Gnomad SAS AF: 0.712

Gnomad FIN AF: 0.575

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.660

GnomAD4 exome AF: 0.628 AC: 607026 AN: 966608 Hom.: 194688 AF XY: 0.630 AC XY: 302699 AN XY: 480380

African (AFR) AF: 0.677 AC: 15291 AN: 22574

American (AMR) AF: 0.733 AC: 18551 AN: 25302

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 12425 AN: 18064

East Asian (EAS) AF: 0.966 AC: 32107 AN: 33250

South Asian (SAS) AF: 0.702 AC: 40733 AN: 57988

European-Finnish (FIN) AF: 0.579 AC: 17593 AN: 30400

Middle Eastern (MID) AF: 0.642 AC: 1953 AN: 3044

European-Non Finnish (NFE) AF: 0.601 AC: 440332 AN: 732866

Other (OTH) AF: 0.650 AC: 28041 AN: 43120

GnomAD4 genome AF: 0.647 AC: 98375 AN: 152158 Hom.: 32463 Cov.: 33 AF XY: 0.648 AC XY: 48216 AN XY: 74380

African (AFR) AF: 0.673 AC: 27913 AN: 41506

American (AMR) AF: 0.703 AC: 10748 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.676 AC: 2344 AN: 3470

East Asian (EAS) AF: 0.942 AC: 4884 AN: 5182

South Asian (SAS) AF: 0.711 AC: 3432 AN: 4826

European-Finnish (FIN) AF: 0.575 AC: 6076 AN: 10576

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.603 AC: 41028 AN: 67984

Other (OTH) AF: 0.663 AC: 1401 AN: 2112

Alfa AF: 0.624 Hom.: 3692

Bravo AF: 0.658

Asia WGS AF: 0.822 AC: 2856 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.28
DANN	Benign	0.59
PhyloP100		-0.90
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: rs4689394; hg19: chr4-6291003;