4-6270243-G-C

Variant names:

• chr4-6270243-G-C
• rs548990311
• NM_006005.3:c.-6+229G>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006005.3(WFS1):​c.-6+229G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00934 in 151,786 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.0093 (32 hom., cov: 32)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.518

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=-0.89).
• BP6: Variant 4-6270243-G-C is Benign according to our data. Variant chr4-6270243-G-C is described in ClinVar as [Benign]. Clinvar id is 1233658.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00934 (1418/151786) while in subpopulation AMR AF= 0.00911 (139/15250). AF 95% confidence interval is 0.00788. There are 32 homozygotes in gnomad4. There are 834 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3	c.-6+229G>C		intron_variant	Intron 1 of 7	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.-2+229G>C		intron_variant	Intron 1 of 7		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.-6+229G>C		intron_variant	Intron 1 of 7	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes AF: 0.00937 AC: 1421 AN: 151678 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.00926

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0610

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.00785

Gnomad OTH AF: 0.0129

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

GnomAD4 genome AF: 0.00934 AC: 1418 AN: 151786 Hom.: 32 Cov.: 32 AF XY: 0.0112 AC XY: 834 AN XY: 74182

Gnomad4 AFR AF: 0.00116

Gnomad4 AMR AF: 0.00911

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0610

Gnomad4 NFE AF: 0.00785

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00778 Hom.: 0

Bravo AF: 0.00549

Asia WGS AF: 0.000870 AC: 3 AN: 3462

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.9
DANN	Benign	0.51

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: rs548990311; hg19: chr4-6271970;