4-6302558-G-A

Position:

• chr4-6302558-G-A

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.*90G>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 0.0929 in 1,575,390 control chromosomes in the GnomAD database, including 7,188 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.083 (576 hom., cov: 36)
  • Exomes 𝑓: 0.094 (6612 hom.)
• Consequence: WFS1 NM_006005.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.696

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 4-6302558-G-A is Benign according to our data. Variant chr4-6302558-G-A is described in ClinVar as [Benign]. Clinvar id is 349334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6302558-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.*90G>A		3_prime_UTR_variant	8/8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.*90G>A		3_prime_UTR_variant	8/8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.*90G>A		3_prime_UTR_variant	8/8	1	NM_006005.3	ENSP00000226760	P2
	ENST00000661896.1	n.1337+1357C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0830 AC: 12623 AN: 152162 Hom.: 576 Cov.: 36

Gnomad AFR AF: 0.0639

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.0833

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.0985

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.0710

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0904

Gnomad OTH AF: 0.0780

GnomAD4 exome AF: 0.0940 AC: 133775 AN: 1423112 Hom.: 6612 Cov.: 32 AF XY: 0.0943 AC XY: 66602 AN XY: 706048

Gnomad4 AFR exome AF: 0.0620

Gnomad4 AMR exome AF: 0.0775

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.101

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.0748

Gnomad4 NFE exome AF: 0.0947

Gnomad4 OTH exome AF: 0.0948

GnomAD4 genome AF: 0.0829 AC: 12625 AN: 152278 Hom.: 576 Cov.: 36 AF XY: 0.0823 AC XY: 6128 AN XY: 74460

Gnomad4 AFR AF: 0.0636

Gnomad4 AMR AF: 0.0832

Gnomad4 ASJ AF: 0.114

Gnomad4 EAS AF: 0.0985

Gnomad4 SAS AF: 0.109

Gnomad4 FIN AF: 0.0710

Gnomad4 NFE AF: 0.0904

Gnomad4 OTH AF: 0.0791

Alfa AF: 0.0818 Hom.: 69

Bravo AF: 0.0838

Asia WGS AF: 0.101 AC: 349 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2018	- -

WFS1-Related Spectrum Disorders Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Autosomal dominant nonsyndromic hearing loss 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	0.69
DANN	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1802453; hg19: chr4-6304285;