4-6302559-C-T

Variant names:

• chr4-6302559-C-T
• rs1046319
• NM_006005.3:c.*91C>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.*91C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.744 in 1,571,184 control chromosomes in the GnomAD database, including 438,336 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45624 hom., cov: 35)
  • Exomes 𝑓: 0.74 (392712 hom.)
• Consequence: WFS1 NM_006005.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.07

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]

ENSG00000286176 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 4-6302559-C-T is Benign according to our data. Variant chr4-6302559-C-T is described in ClinVar as [Benign]. Clinvar id is 349335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6302559-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3	c.*91C>T		3_prime_UTR_variant	Exon 8 of 8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.*91C>T		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.*91C>T		3_prime_UTR_variant	Exon 8 of 8	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes AF: 0.770 AC: 117147 AN: 152066 Hom.: 45580 Cov.: 35

Gnomad AFR AF: 0.837

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.787

Gnomad ASJ AF: 0.813

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.846

Gnomad FIN AF: 0.661

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.721

Gnomad OTH AF: 0.761

GnomAD4 exome AF: 0.741 AC: 1052142 AN: 1419002 Hom.: 392712 Cov.: 28 AF XY: 0.744 AC XY: 523218 AN XY: 703518

Gnomad4 AFR exome AF: 0.839

Gnomad4 AMR exome AF: 0.804

Gnomad4 ASJ exome AF: 0.816

Gnomad4 EAS exome AF: 0.998

Gnomad4 SAS exome AF: 0.832

Gnomad4 FIN exome AF: 0.672

Gnomad4 NFE exome AF: 0.719

Gnomad4 OTH exome AF: 0.767

GnomAD4 genome AF: 0.770 AC: 117249 AN: 152182 Hom.: 45624 Cov.: 35 AF XY: 0.770 AC XY: 57314 AN XY: 74392

Gnomad4 AFR AF: 0.838

Gnomad4 AMR AF: 0.787

Gnomad4 ASJ AF: 0.813

Gnomad4 EAS AF: 0.996

Gnomad4 SAS AF: 0.845

Gnomad4 FIN AF: 0.661

Gnomad4 NFE AF: 0.721

Gnomad4 OTH AF: 0.764

Alfa AF: 0.752 Hom.: 10454

Bravo AF: 0.782

Asia WGS AF: 0.917 AC: 3189 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

- -

-

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	-0.94
CADD	Benign	0.41
DANN	Benign	0.52
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: rs1046319; hg19: chr4-6304286;