4-6277320-C-T

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.-5-131C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.806 in 866,530 control chromosomes in the GnomAD database, including 282,898 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.82 (50814 hom., cov: 34)
  • Exomes 𝑓: 0.80 (232084 hom.)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.899

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=-0.92).
• BP6: Variant 4-6277320-C-T is Benign according to our data. Variant chr4-6277320-C-T is described in ClinVar as [Benign]. Clinvar id is 1257985.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.922 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3	c.-5-131C>T		intron_variant		ENST00000226760.5
WFS1	NM_001145853.1	c.-1-135C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.-5-131C>T		intron_variant		1	NM_006005.3	P2

Frequencies

GnomAD3 genomes AF: 0.815 AC: 124027 AN: 152098 Hom.: 50767 Cov.: 34

Gnomad AFR AF: 0.833

Gnomad AMI AF: 0.834

Gnomad AMR AF: 0.859

Gnomad ASJ AF: 0.845

Gnomad EAS AF: 0.944

Gnomad SAS AF: 0.822

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.792

Gnomad OTH AF: 0.838

GnomAD4 exome AF: 0.804 AC: 574508 AN: 714314 Hom.: 232084 AF XY: 0.804 AC XY: 299047 AN XY: 371774

Gnomad4 AFR exome AF: 0.831

Gnomad4 AMR exome AF: 0.878

Gnomad4 ASJ exome AF: 0.856

Gnomad4 EAS exome AF: 0.968

Gnomad4 SAS exome AF: 0.817

Gnomad4 FIN exome AF: 0.758

Gnomad4 NFE exome AF: 0.786

Gnomad4 OTH exome AF: 0.812

GnomAD4 genome AF: 0.816 AC: 124133 AN: 152216 Hom.: 50814 Cov.: 34 AF XY: 0.815 AC XY: 60608 AN XY: 74406

Gnomad4 AFR AF: 0.833

Gnomad4 AMR AF: 0.859

Gnomad4 ASJ AF: 0.845

Gnomad4 EAS AF: 0.944

Gnomad4 SAS AF: 0.823

Gnomad4 FIN AF: 0.752

Gnomad4 NFE AF: 0.792

Gnomad4 OTH AF: 0.838

Alfa AF: 0.789 Hom.: 4590

Bravo AF: 0.825

Asia WGS AF: 0.879 AC: 3057 AN: 3478

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	-0.92
Cadd	Benign	0.15
Dann	Benign	0.50

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: rs10937714; hg19: chr4-6279047;