4-6294720-G-T

Variant names:

• chr4-6294720-G-T
• rs12511742
• NM_006005.3:c.713-321G>T

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.713-321G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0626 in 392,278 control chromosomes in the GnomAD database, including 1,045 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (343 hom., cov: 33)
  • Exomes 𝑓: 0.067 (702 hom.)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.874
• Publications: 7 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)

ENSG00000286176 (HGNC:58722):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 4-6294720-G-T is Benign according to our data. Variant chr4-6294720-G-T is described in ClinVar as Benign. ClinVar VariationId is 673197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3	c.713-321G>T		intron_variant	Intron 6 of 7	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.713-321G>T		intron_variant	Intron 6 of 7		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.713-321G>T		intron_variant	Intron 6 of 7	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes AF: 0.0558 AC: 8486 AN: 152128 Hom.: 344 Cov.: 33

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0608

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.0491

Gnomad FIN AF: 0.0650

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0713

Gnomad OTH AF: 0.0431

GnomAD4 exome AF: 0.0670 AC: 16086 AN: 240032 Hom.: 702 AF XY: 0.0643 AC XY: 8277 AN XY: 128636

African (AFR) AF: 0.0154 AC: 107 AN: 6940

American (AMR) AF: 0.0800 AC: 971 AN: 12134

Ashkenazi Jewish (ASJ) AF: 0.0296 AC: 195 AN: 6578

East Asian (EAS) AF: 0.170 AC: 2021 AN: 11894

South Asian (SAS) AF: 0.0394 AC: 1629 AN: 41392

European-Finnish (FIN) AF: 0.0698 AC: 776 AN: 11116

Middle Eastern (MID) AF: 0.0179 AC: 16 AN: 894

European-Non Finnish (NFE) AF: 0.0702 AC: 9577 AN: 136360

Other (OTH) AF: 0.0624 AC: 794 AN: 12724

GnomAD4 genome AF: 0.0557 AC: 8482 AN: 152246 Hom.: 343 Cov.: 33 AF XY: 0.0563 AC XY: 4188 AN XY: 74430

African (AFR) AF: 0.0157 AC: 652 AN: 41558

American (AMR) AF: 0.0608 AC: 931 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0308 AC: 107 AN: 3472

East Asian (EAS) AF: 0.177 AC: 911 AN: 5156

South Asian (SAS) AF: 0.0487 AC: 235 AN: 4824

European-Finnish (FIN) AF: 0.0650 AC: 691 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0713 AC: 4847 AN: 67988

Other (OTH) AF: 0.0426 AC: 90 AN: 2112

Alfa AF: 0.0643 Hom.: 302

Bravo AF: 0.0557

Asia WGS AF: 0.0890 AC: 311 AN: 3478

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 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.37
DANN	Benign	0.54
PhyloP100		-0.87
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs12511742; hg19: chr4-6296447;