4-6270099-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006005.3(WFS1):c.-6+85T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.585 in 151,706 control chromosomes in the GnomAD database, including 26,667 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.59 (26643 hom., cov: 34)
  • Exomes 𝑓: 0.58 (24 hom.)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.596

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 4-6270099-T-C is Benign according to our data. Variant chr4-6270099-T-C is described in ClinVar as [Benign]. Clinvar id is 1292283.Status of the report is criteria_provided_single_submitter, 1 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.-6+85T>C		intron_variant		ENST00000226760.5
WFS1	NM_001145853.1	c.-2+85T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.-6+85T>C		intron_variant		1	NM_006005.3	P2

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88648 AN: 151480 Hom.: 26620 Cov.: 34

Gnomad AFR AF: 0.518

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.662

Gnomad ASJ AF: 0.666

Gnomad EAS AF: 0.933

Gnomad SAS AF: 0.669

Gnomad FIN AF: 0.550

Gnomad MID AF: 0.619

Gnomad NFE AF: 0.579

Gnomad OTH AF: 0.608

GnomAD4 exome AF: 0.576 AC: 68 AN: 118 Hom.: 24 AF XY: 0.563 AC XY: 54 AN XY: 96

Gnomad4 AFR exome AF: 0.750

Gnomad4 AMR exome AF: 1.00

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.538

GnomAD4 genome AF: 0.585 AC: 88710 AN: 151588 Hom.: 26643 Cov.: 34 AF XY: 0.589 AC XY: 43643 AN XY: 74106

Gnomad4 AFR AF: 0.518

Gnomad4 AMR AF: 0.663

Gnomad4 ASJ AF: 0.666

Gnomad4 EAS AF: 0.934

Gnomad4 SAS AF: 0.670

Gnomad4 FIN AF: 0.550

Gnomad4 NFE AF: 0.579

Gnomad4 OTH AF: 0.610

Alfa AF: 0.581 Hom.: 3202

Bravo AF: 0.590

Asia WGS AF: 0.770 AC: 2669 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	6.8
Dann	Benign	0.32

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: rs6830765; hg19: chr4-6271826;