rs9457

Variant names:

• chr4-6303072-G-C
• rs9457
• NM_006005.3:c.*604G>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.*604G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 157,996 control chromosomes in the GnomAD database, including 24,993 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23856 hom., cov: 32)
  • Exomes 𝑓: 0.60 (1137 hom.)
• Consequence: WFS1 NM_006005.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.114
• Publications: 20 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=-0.9).
• BP6: Variant 4-6303072-G-C is Benign according to our data. Variant chr4-6303072-G-C is described in ClinVar as Benign. ClinVar VariationId is 349354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3	c.*604G>C		3_prime_UTR_variant	Exon 8 of 8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.*604G>C		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.*604G>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes AF: 0.549 AC: 83326 AN: 151842 Hom.: 23838 Cov.: 32

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.629

Gnomad ASJ AF: 0.592

Gnomad EAS AF: 0.932

Gnomad SAS AF: 0.631

Gnomad FIN AF: 0.552

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.559

Gnomad OTH AF: 0.569

GnomAD4 exome AF: 0.603 AC: 3640 AN: 6036 Hom.: 1137 Cov.: 0 AF XY: 0.602 AC XY: 1843 AN XY: 3060

African (AFR) AF: 0.438 AC: 7 AN: 16

American (AMR) AF: 0.678 AC: 1184 AN: 1746

Ashkenazi Jewish (ASJ) AF: 0.625 AC: 15 AN: 24

East Asian (EAS) AF: 0.929 AC: 236 AN: 254

South Asian (SAS) AF: 0.585 AC: 329 AN: 562

European-Finnish (FIN) AF: 0.438 AC: 14 AN: 32

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.549 AC: 1736 AN: 3164

Other (OTH) AF: 0.500 AC: 119 AN: 238

GnomAD4 genome AF: 0.549 AC: 83368 AN: 151960 Hom.: 23856 Cov.: 32 AF XY: 0.552 AC XY: 40985 AN XY: 74260

African (AFR) AF: 0.443 AC: 18350 AN: 41446

American (AMR) AF: 0.630 AC: 9630 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.592 AC: 2056 AN: 3472

East Asian (EAS) AF: 0.933 AC: 4791 AN: 5136

South Asian (SAS) AF: 0.633 AC: 3049 AN: 4820

European-Finnish (FIN) AF: 0.552 AC: 5817 AN: 10540

Middle Eastern (MID) AF: 0.565 AC: 165 AN: 292

European-Non Finnish (NFE) AF: 0.559 AC: 37958 AN: 67942

Other (OTH) AF: 0.571 AC: 1204 AN: 2108

Alfa AF: 0.551 Hom.: 2904

Bravo AF: 0.551

Asia WGS AF: 0.745 AC: 2592 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.90
CADD	Benign	1.2
DANN	Benign	0.70
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9457; hg19: chr4-6304799;