rs6824720

Positions:

• chr4-6276920-A-G
• chr4-6276920-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006005.3(WFS1):​c.-5-531A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.851 in 152,276 control chromosomes in the GnomAD database, including 55,314 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.85 (55314 hom., cov: 34)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.90

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.923 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.-5-531A>G		intron_variant		ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.-1-535A>G		intron_variant			NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.-5-531A>G		intron_variant		1	NM_006005.3	ENSP00000226760	P2

Frequencies

GnomAD3 genomes AF: 0.851 AC: 129415 AN: 152158 Hom.: 55256 Cov.: 34

Gnomad AFR AF: 0.882

Gnomad AMI AF: 0.839

Gnomad AMR AF: 0.888

Gnomad ASJ AF: 0.884

Gnomad EAS AF: 0.944

Gnomad SAS AF: 0.850

Gnomad FIN AF: 0.764

Gnomad MID AF: 0.892

Gnomad NFE AF: 0.827

Gnomad OTH AF: 0.869

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.851 AC: 129532 AN: 152276 Hom.: 55314 Cov.: 34 AF XY: 0.849 AC XY: 63212 AN XY: 74440

Gnomad4 AFR AF: 0.883

Gnomad4 AMR AF: 0.888

Gnomad4 ASJ AF: 0.884

Gnomad4 EAS AF: 0.945

Gnomad4 SAS AF: 0.850

Gnomad4 FIN AF: 0.764

Gnomad4 NFE AF: 0.827

Gnomad4 OTH AF: 0.869

Alfa AF: 0.825 Hom.: 5137

Bravo AF: 0.861

Asia WGS AF: 0.895 AC: 3115 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.45

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: rs6824720; hg19: chr4-6278647;