rs2272068

Positions:

chr2-26476954-G-A

Variant summary

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

The NM_194248.3(OTOF):c.2613C>T(p.Leu871Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0226 in 1,611,540 control chromosomes in the GnomAD database, including 940 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 136 hom., cov: 26)

Exomes 𝑓: 0.021 ( 804 hom. )

Consequence

OTOF
NM_194248.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0400

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=-0.4).

BP6

Variant 2-26476954-G-A is Benign according to our data. Variant chr2-26476954-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 48203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26476954-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.04 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.132 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.2613C>T	p.Leu871Leu	synonymous_variant	22/47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 linkuse as main transcript	c.372C>T	p.Leu124Leu	synonymous_variant	5/29	ENST00000339598.8	NP_919304.1	Q9HC10-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.2613C>T	p.Leu871Leu	synonymous_variant	22/47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 linkuse as main transcript	c.372C>T	p.Leu124Leu	synonymous_variant	5/29	1	NM_194323.3	ENSP00000344521.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.0347

AC:

5252

AN:

151530

Hom.:

134

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0526

Gnomad AMI

AF:

0.138

Gnomad AMR

AF:

0.0365

Gnomad ASJ

AF:

0.00318

Gnomad EAS

AF:

0.140

Gnomad SAS

AF:

0.0499

Gnomad FIN

AF:

0.0421

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.0137

Gnomad OTH

AF:

0.0278

GnomAD3 exomes

AF:

0.0344

AC:

8576

AN:

249658

Hom.:

290

AF XY:

0.0334

AC XY:

4532

AN XY:

135574

show subpopulations

Gnomad AFR exome

AF:

0.0523

Gnomad AMR exome

AF:

0.0395

Gnomad ASJ exome

AF:

0.00190

Gnomad EAS exome

AF:

0.136

Gnomad SAS exome

AF:

0.0445

Gnomad FIN exome

AF:

0.0389

Gnomad NFE exome

AF:

0.0133

Gnomad OTH exome

AF:

0.0256

GnomAD4 exome

AF:

0.0214

AC:

31233

AN:

1459894

Hom.:

804

Cov.:

AF XY:

0.0219

AC XY:

15905

AN XY:

726256

show subpopulations

Gnomad4 AFR exome

AF:

0.0557

Gnomad4 AMR exome

AF:

0.0402

Gnomad4 ASJ exome

AF:

0.00176

Gnomad4 EAS exome

AF:

0.140

Gnomad4 SAS exome

AF:

0.0442

Gnomad4 FIN exome

AF:

0.0347

Gnomad4 NFE exome

AF:

0.0131

Gnomad4 OTH exome

AF:

0.0284

GnomAD4 genome

AF:

0.0347

AC:

5266

AN:

151646

Hom.:

136

Cov.:

AF XY:

0.0363

AC XY:

2694

AN XY:

74166

show subpopulations

Gnomad4 AFR

AF:

0.0529

Gnomad4 AMR

AF:

0.0364

Gnomad4 ASJ

AF:

0.00318

Gnomad4 EAS

AF:

0.140

Gnomad4 SAS

AF:

0.0493

Gnomad4 FIN

AF:

0.0421

Gnomad4 NFE

AF:

0.0138

Gnomad4 OTH

AF:

0.0270

Alfa

AF:

0.0182

Hom.:

Bravo

AF:

0.0357

Asia WGS

AF:

0.0960

AC:

333

AN:

3478

EpiCase

AF:

0.0132

EpiControl

AF:

0.0131

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 19, 2008	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Autosomal recessive nonsyndromic hearing loss 9

Benign:1

Likely 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 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

-0.40

CADD

Benign

7.4

DANN

Benign

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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