rs1046320

Positions:

• chr4-6302617-G-A
• chr4-6302617-G-T

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.*149G>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 0.595 in 1,162,182 control chromosomes in the GnomAD database, including 209,854 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (24255 hom., cov: 32)
  • Exomes 𝑓: 0.60 (185599 hom.)
• Consequence: WFS1 NM_006005.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.728

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 4-6302617-G-A is Benign according to our data. Variant chr4-6302617-G-A is described in ClinVar as [Benign]. Clinvar id is 349337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.873 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.*149G>A		3_prime_UTR_variant	8/8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.*149G>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.*149G>A		3_prime_UTR_variant	8/8	1	NM_006005.3	ENSP00000226760	P2
	ENST00000661896.1	n.1337+1298C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.549 AC: 83255 AN: 151684 Hom.: 24241 Cov.: 32

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.657

Gnomad ASJ AF: 0.670

Gnomad EAS AF: 0.894

Gnomad SAS AF: 0.649

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.593

Gnomad OTH AF: 0.580

GnomAD4 exome AF: 0.601 AC: 607682 AN: 1010380 Hom.: 185599 Cov.: 13 AF XY: 0.604 AC XY: 303064 AN XY: 501438

Gnomad4 AFR exome AF: 0.366

Gnomad4 AMR exome AF: 0.709

Gnomad4 ASJ exome AF: 0.682

Gnomad4 EAS exome AF: 0.932

Gnomad4 SAS exome AF: 0.646

Gnomad4 FIN exome AF: 0.570

Gnomad4 NFE exome AF: 0.585

Gnomad4 OTH exome AF: 0.609

GnomAD4 genome AF: 0.549 AC: 83287 AN: 151802 Hom.: 24255 Cov.: 32 AF XY: 0.553 AC XY: 41036 AN XY: 74172

Gnomad4 AFR AF: 0.369

Gnomad4 AMR AF: 0.658

Gnomad4 ASJ AF: 0.670

Gnomad4 EAS AF: 0.894

Gnomad4 SAS AF: 0.649

Gnomad4 FIN AF: 0.562

Gnomad4 NFE AF: 0.593

Gnomad4 OTH AF: 0.582

Alfa AF: 0.564 Hom.: 9758

Bravo AF: 0.549

Asia WGS AF: 0.737 AC: 2565 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	clinical testing	GeneDx	Jun 23, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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. -

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	0.77
DANN	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1046320; hg19: chr4-6304344;