rs4665855

Variant names:

Variant summary

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

The NM_194322.3(OTOF):c.62C>T(p.Pro21Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 1,576,720 control chromosomes in the GnomAD database, including 163,722 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 18095 hom., cov: 32)

Exomes 𝑓: 0.44 ( 145627 hom. )

Consequence

OTOF
NM_194322.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.327

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2123064E-6).

BP6

Variant 2-26477832-G-A is Benign according to our data. Variant chr2-26477832-G-A is described in ClinVar as [Benign]. Clinvar id is 48191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26477832-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.2215-83C>T		intron_variant	Intron 18 of 46	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 link	c.-28+12C>T		intron_variant	Intron 1 of 28	ENST00000339598.8	NP_919304.1	Q9HC10-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 link	c.2215-83C>T		intron_variant	Intron 18 of 46	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 link	c.-28+12C>T		intron_variant	Intron 1 of 28	1	NM_194323.3	ENSP00000344521.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.471

AC:

71619

AN:

151918

Hom.:

18076

Cov.:

show subpopulations

Gnomad AFR

AF:

0.453

Gnomad AMI

AF:

0.557

Gnomad AMR

AF:

0.573

Gnomad ASJ

AF:

0.359

Gnomad EAS

AF:

0.984

Gnomad SAS

AF:

0.563

Gnomad FIN

AF:

0.594

Gnomad MID

AF:

0.291

Gnomad NFE

AF:

0.402

Gnomad OTH

AF:

0.440

GnomAD3 exomes

AF:

0.524

AC:

101448

AN:

193584

Hom.:

29309

AF XY:

0.516

AC XY:

53561

AN XY:

103792

show subpopulations

Gnomad AFR exome

AF:

0.458

Gnomad AMR exome

AF:

0.688

Gnomad ASJ exome

AF:

0.354

Gnomad EAS exome

AF:

0.987

Gnomad SAS exome

AF:

0.541

Gnomad FIN exome

AF:

0.579

Gnomad NFE exome

AF:

0.402

Gnomad OTH exome

AF:

0.459

GnomAD4 exome

AF:

0.438

AC:

623898

AN:

1424682

Hom.:

145627

Cov.:

AF XY:

0.440

AC XY:

310290

AN XY:

705488

show subpopulations

Gnomad4 AFR exome

AF:

0.447

Gnomad4 AMR exome

AF:

0.670

Gnomad4 ASJ exome

AF:

0.355

Gnomad4 EAS exome

AF:

0.976

Gnomad4 SAS exome

AF:

0.540

Gnomad4 FIN exome

AF:

0.564

Gnomad4 NFE exome

AF:

0.399

Gnomad4 OTH exome

AF:

0.461

GnomAD4 genome

AF:

0.471

AC:

71682

AN:

152038

Hom.:

18095

Cov.:

AF XY:

0.484

AC XY:

35978

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.453

Gnomad4 AMR

AF:

0.574

Gnomad4 ASJ

AF:

0.359

Gnomad4 EAS

AF:

0.984

Gnomad4 SAS

AF:

0.564

Gnomad4 FIN

AF:

0.594

Gnomad4 NFE

AF:

0.402

Gnomad4 OTH

AF:

0.445

Alfa

AF:

0.425

Hom.:

16065

Bravo

AF:

0.471

TwinsUK

AF:

0.382

AC:

1415

ALSPAC

AF:

0.405

AC:

1560

ESP6500AA

AF:

0.440

AC:

1167

ESP6500EA

AF:

0.394

AC:

1821

ExAC

AF:

0.472

AC:

55243

Asia WGS

AF:

0.746

AC:

2589

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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	May 07, 2012	Pro21Leu in exon 1 of OTOF: This variant is not expected to have clinical signif icance because it is has been identified in 5.4% (337/6988) of European American chromosomes and 28.3% (1051/3718) of African American chromosomes from a broad population by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/E VS/; dbSNP rs4665855). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

1.0

DANN

Benign

0.65

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0000012

MetaSVM

Benign

-1.0

Polyphen

0.0

ClinPred

0.025

GERP RS

-0.57

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