rs5018647

Positions:

• chr4-6291072-A-C
• chr4-6291072-A-G
• chr4-6291072-A-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.461-125A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 1,098,338 control chromosomes in the GnomAD database, including 202,603 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31732 hom., cov: 32)
  • Exomes 𝑓: 0.59 (170871 hom.)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0460

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 4-6291072-A-C is Benign according to our data. Variant chr4-6291072-A-C is described in ClinVar as [Benign]. Clinvar id is 1292285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.919 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.461-125A>C		intron_variant		ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.461-125A>C		intron_variant			NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.461-125A>C		intron_variant		1	NM_006005.3	ENSP00000226760	P2

Frequencies

GnomAD3 genomes AF: 0.640 AC: 97112 AN: 151706 Hom.: 31690 Cov.: 32

Gnomad AFR AF: 0.655

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.701

Gnomad ASJ AF: 0.678

Gnomad EAS AF: 0.940

Gnomad SAS AF: 0.711

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.601

Gnomad OTH AF: 0.658

GnomAD4 exome AF: 0.594 AC: 562287 AN: 946512 Hom.: 170871 AF XY: 0.599 AC XY: 291542 AN XY: 487092

Gnomad4 AFR exome AF: 0.634

Gnomad4 AMR exome AF: 0.734

Gnomad4 ASJ exome AF: 0.682

Gnomad4 EAS exome AF: 0.963

Gnomad4 SAS exome AF: 0.687

Gnomad4 FIN exome AF: 0.573

Gnomad4 NFE exome AF: 0.553

Gnomad4 OTH exome AF: 0.623

GnomAD4 genome AF: 0.640 AC: 97207 AN: 151826 Hom.: 31732 Cov.: 32 AF XY: 0.643 AC XY: 47688 AN XY: 74168

Gnomad4 AFR AF: 0.655

Gnomad4 AMR AF: 0.702

Gnomad4 ASJ AF: 0.678

Gnomad4 EAS AF: 0.941

Gnomad4 SAS AF: 0.710

Gnomad4 FIN AF: 0.573

Gnomad4 NFE AF: 0.601

Gnomad4 OTH AF: 0.661

Alfa AF: 0.523 Hom.: 1812

Bravo AF: 0.651

Asia WGS AF: 0.820 AC: 2851 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.7
DANN	Benign	0.69

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: rs5018647; hg19: chr4-6292799;