Variant chr2-26457542-T-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_194248.3(OTOF):c.*696A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0445 in 153,904 control chromosomes in the GnomAD database, including 479 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 478 hom., cov: 33)

Exomes 𝑓: 0.0054 ( 1 hom. )

Consequence

OTOF
NM_194248.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.86

Variant links:

Genes affected

OTOF (HGNC:8515): (otoferlin) Mutations in this gene are a cause of neurosensory nonsyndromic recessive deafness, DFNB9. The short form of the encoded protein has 3 C2 domains, a single carboxy-terminal transmembrane domain found also in the C. elegans spermatogenesis factor FER-1 and human dysferlin, while the long form has 6 C2 domains. The homology suggests that this protein may be involved in vesicle membrane fusion. Several transcript variants encoding multiple isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OTOF 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=-0.87).

BP6

Variant 2-26457542-T-C is Benign according to our data. Variant chr2-26457542-T-C is described in ClinVar as [Benign]. Clinvar id is 335423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.*696A>G		3_prime_UTR_variant	47/47	ENST00000272371.7
OTOF	NM_194323.3 linkuse as main transcript	c.*498A>G		3_prime_UTR_variant	29/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.*696A>G		3_prime_UTR_variant	47/47	1	NM_194248.3	A1	Q9HC10-1
OTOF	ENST00000339598.8 linkuse as main transcript	c.*498A>G		3_prime_UTR_variant	29/29	1	NM_194323.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.0449

AC:

6829

AN:

152104

Hom.:

477

Cov.:

show subpopulations

Gnomad AFR

AF:

0.152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0226

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00517

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0258

Gnomad NFE

AF:

0.00160

Gnomad OTH

AF:

0.0325

GnomAD4 exome

AF:

0.00536

AC:

AN:

1680

Hom.:

Cov.:

AF XY:

0.00445

AC XY:

AN XY:

898

show subpopulations

Gnomad4 AFR exome

AF:

0.208

Gnomad4 AMR exome

AF:

0.0200

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0450

AC:

6843

AN:

152224

Hom.:

478

Cov.:

AF XY:

0.0425

AC XY:

3162

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.151

Gnomad4 AMR

AF:

0.0225

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00518

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00159

Gnomad4 OTH

AF:

0.0322

Alfa

AF:

0.0194

Hom.:

Bravo

AF:

0.0510

Asia WGS

AF:

0.00924

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 9

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.21

DANN

Benign

0.26

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

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