rs73920285

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The ENST00000272371.7(OTOF):c.2829C>T(p.Gly943=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00709 in 1,611,102 control chromosomes in the GnomAD database, including 629 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 326 hom., cov: 32)

Exomes 𝑓: 0.0040 ( 303 hom. )

Consequence

OTOF
ENST00000272371.7 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.306

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 2-26476165-G-A is Benign according to our data. Variant chr2-26476165-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 48206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26476165-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.306 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.2829C>T	p.Gly943=	synonymous_variant	23/47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3 linkuse as main transcript	c.588C>T	p.Gly196=	synonymous_variant	6/29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.2829C>T	p.Gly943=	synonymous_variant	23/47	1	NM_194248.3	ENSP00000272371	A1	Q9HC10-1
OTOF	ENST00000339598.8 linkuse as main transcript	c.588C>T	p.Gly196=	synonymous_variant	6/29	1	NM_194323.3	ENSP00000344521		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.0366

AC:

5565

AN:

152044

Hom.:

327

Cov.:

show subpopulations

Gnomad AFR

AF:

0.126

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0158

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.0263

GnomAD3 exomes

AF:

0.00967

AC:

2387

AN:

246862

Hom.:

135

AF XY:

0.00709

AC XY:

952

AN XY:

134290

show subpopulations

Gnomad AFR exome

AF:

0.130

Gnomad AMR exome

AF:

0.00604

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.0000486

Gnomad NFE exome

AF:

0.000684

Gnomad OTH exome

AF:

0.00496

GnomAD4 exome

AF:

0.00401

AC:

5850

AN:

1458940

Hom.:

303

Cov.:

AF XY:

0.00343

AC XY:

2493

AN XY:

725780

show subpopulations

Gnomad4 AFR exome

AF:

0.129

Gnomad4 AMR exome

AF:

0.00689

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000186

Gnomad4 FIN exome

AF:

0.0000392

Gnomad4 NFE exome

AF:

0.000560

Gnomad4 OTH exome

AF:

0.00856

GnomAD4 genome

AF:

0.0366

AC:

5574

AN:

152162

Hom.:

326

Cov.:

AF XY:

0.0356

AC XY:

2646

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.126

Gnomad4 AMR

AF:

0.0158

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.0260

Alfa

AF:

0.0131

Hom.:

Bravo

AF:

0.0416

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000712

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 25, 2011	Gly943Gly in exon 23 of OTOF: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located near a splice junction, is listed in dbSNP (rs73920285- no frequency data) and has been observed in 5/240 (2%) cases. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive nonsyndromic hearing loss 9

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

2.9

DANN

Benign

0.61

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