Variant 4-6303072-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006005.3(WFS1):c.*604G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 157,996 control chromosomes in the GnomAD database, including 24,993 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 23856 hom., cov: 32)

Exomes 𝑓: 0.60 ( 1137 hom. )

Consequence

WFS1
NM_006005.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.114

Variant links:

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]

WFS1 links:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 4-6303072-G-C is Benign according to our data. Variant chr4-6303072-G-C is described in ClinVar as [Benign]. Clinvar id is 349354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3 linkuse as main transcript	c.*604G>C		3_prime_UTR_variant	8/8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1 linkuse as main transcript	c.*604G>C		3_prime_UTR_variant	8/8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5 linkuse as main transcript	c.*604G>C		3_prime_UTR_variant	8/8	1	NM_006005.3	ENSP00000226760	P2
	ENST00000661896.1 linkuse as main transcript	n.1337+843C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.549

AC:

83326

AN:

151842

Hom.:

23838

Cov.:

show subpopulations

Gnomad AFR

AF:

0.443

Gnomad AMI

AF:

0.382

Gnomad AMR

AF:

0.629

Gnomad ASJ

AF:

0.592

Gnomad EAS

AF:

0.932

Gnomad SAS

AF:

0.631

Gnomad FIN

AF:

0.552

Gnomad MID

AF:

0.573

Gnomad NFE

AF:

0.559

Gnomad OTH

AF:

0.569

GnomAD4 exome

AF:

0.603

AC:

3640

AN:

6036

Hom.:

1137

Cov.:

AF XY:

0.602

AC XY:

1843

AN XY:

3060

show subpopulations

Gnomad4 AFR exome

AF:

0.438

Gnomad4 AMR exome

AF:

0.678

Gnomad4 ASJ exome

AF:

0.625

Gnomad4 EAS exome

AF:

0.929

Gnomad4 SAS exome

AF:

0.585

Gnomad4 FIN exome

AF:

0.438

Gnomad4 NFE exome

AF:

0.549

Gnomad4 OTH exome

AF:

0.500

GnomAD4 genome

AF:

0.549

AC:

83368

AN:

151960

Hom.:

23856

Cov.:

AF XY:

0.552

AC XY:

40985

AN XY:

74260

show subpopulations

Gnomad4 AFR

AF:

0.443

Gnomad4 AMR

AF:

0.630

Gnomad4 ASJ

AF:

0.592

Gnomad4 EAS

AF:

0.933

Gnomad4 SAS

AF:

0.633

Gnomad4 FIN

AF:

0.552

Gnomad4 NFE

AF:

0.559

Gnomad4 OTH

AF:

0.571

Alfa

AF:

0.551

Hom.:

2904

Bravo

AF:

0.551

Asia WGS

AF:

0.745

AC:

2592

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

WFS1-Related Spectrum Disorders

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Autosomal dominant nonsyndromic hearing loss 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.2

DANN

Benign

0.70

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over