rs9457

Positions:

• chr4-6303072-G-C

Variant summary

Our verdict is Benign. Variant got -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

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
WFS1	NM_006005.3	c.*604G>C		3_prime_UTR_variant	8/8	ENST00000226760.5
WFS1	NM_001145853.1	c.*604G>C		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.*604G>C		3_prime_UTR_variant	8/8	1	NM_006005.3	P2
	ENST00000661896.1	n.1337+843C>G		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR exome AF: 0.438

Gnomad4 AMR exome AF: 0.678

Gnomad4 ASJ exome AF: 0.625

Gnomad4 EAS exome AF: 0.929

Gnomad4 SAS exome AF: 0.585

Gnomad4 FIN exome AF: 0.438

Gnomad4 NFE exome AF: 0.549

Gnomad4 OTH exome AF: 0.500

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

Gnomad4 AFR AF: 0.443

Gnomad4 AMR AF: 0.630

Gnomad4 ASJ AF: 0.592

Gnomad4 EAS AF: 0.933

Gnomad4 SAS AF: 0.633

Gnomad4 FIN AF: 0.552

Gnomad4 NFE AF: 0.559

Gnomad4 OTH AF: 0.571

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Autosomal dominant nonsyndromic hearing loss 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs9457; hg19: chr4-6304799;