rs1046322

Variant names:

• chr4-6302721-G-A
• rs1046322
• NM_006005.3:c.*253G>A

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.*253G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 597,980 control chromosomes in the GnomAD database, including 3,717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (794 hom., cov: 33)
  • Exomes 𝑓: 0.11 (2923 hom.)
• Consequence: WFS1 NM_006005.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.00
• Publications: 28 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=-0.84).
• BP6: Variant 4-6302721-G-A is Benign according to our data. Variant chr4-6302721-G-A is described in ClinVar as Benign. ClinVar VariationId is 349340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3	c.*253G>A		3_prime_UTR_variant	Exon 8 of 8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.*253G>A		3_prime_UTR_variant	Exon 8 of 8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.*253G>A		3_prime_UTR_variant	Exon 8 of 8	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes AF: 0.0973 AC: 14804 AN: 152194 Hom.: 795 Cov.: 33

Gnomad AFR AF: 0.0654

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.0871

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.0697

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0865

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.106

GnomAD4 exome AF: 0.110 AC: 48995 AN: 445668 Hom.: 2923 Cov.: 5 AF XY: 0.111 AC XY: 25653 AN XY: 232038

African (AFR) AF: 0.0684 AC: 848 AN: 12396

American (AMR) AF: 0.0725 AC: 1220 AN: 16830

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 1669 AN: 13264

East Asian (EAS) AF: 0.0743 AC: 2178 AN: 29326

South Asian (SAS) AF: 0.117 AC: 5053 AN: 43302

European-Finnish (FIN) AF: 0.0891 AC: 2461 AN: 27628

Middle Eastern (MID) AF: 0.163 AC: 309 AN: 1900

European-Non Finnish (NFE) AF: 0.118 AC: 32414 AN: 275496

Other (OTH) AF: 0.111 AC: 2843 AN: 25526

GnomAD4 genome AF: 0.0973 AC: 14815 AN: 152312 Hom.: 794 Cov.: 33 AF XY: 0.0949 AC XY: 7067 AN XY: 74476

African (AFR) AF: 0.0654 AC: 2720 AN: 41566

American (AMR) AF: 0.0869 AC: 1330 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 477 AN: 3470

East Asian (EAS) AF: 0.0694 AC: 360 AN: 5184

South Asian (SAS) AF: 0.118 AC: 570 AN: 4830

European-Finnish (FIN) AF: 0.0865 AC: 919 AN: 10620

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7968 AN: 68010

Other (OTH) AF: 0.106 AC: 224 AN: 2116

Alfa AF: 0.112 Hom.: 1606

Bravo AF: 0.0969

Asia WGS AF: 0.0920 AC: 317 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23650218) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

WFS1-Related Spectrum Disorders Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal dominant nonsyndromic hearing loss 6 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.2
DANN	Benign	0.47
PhyloP100		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		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: rs1046322; hg19: chr4-6304448; COSMIC: COSV56988195; COSMIC: COSV56988195;