rs55676840

Positions:

chr2-26480866-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 1269/30610) of the c.1723G>A (p.Val575Met) variant in the OTOF gene is 3.95% for South Asian chromosome in gnomAD v2.1.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA142762/MONDO:0019497/005

Frequency

Genomes: 𝑓 0.0089 ( 17 hom., cov: 33)

Exomes 𝑓: 0.012 ( 177 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:9O:1

Conservation

PhyloP100: 5.00

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 -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.1723G>A	p.Val575Met	missense_variant	15/47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_001287489.2 link	c.1723G>A	p.Val575Met	missense_variant	15/46		NP_001274418.1	Q9HC10-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 link	c.1723G>A	p.Val575Met	missense_variant	15/47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000403946.7 link	c.1723G>A	p.Val575Met	missense_variant	15/46	5		ENSP00000385255.3		Q9HC10-5

Frequencies

GnomAD3 genomes

AF:

0.00887

AC:

1350

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00236

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.00379

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0435

Gnomad FIN

AF:

0.00847

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0122

Gnomad OTH

AF:

0.00718

GnomAD3 exomes

AF:

0.0121

AC:

3025

AN:

249328

Hom.:

AF XY:

0.0134

AC XY:

1819

AN XY:

135344

show subpopulations

Gnomad AFR exome

AF:

0.00192

Gnomad AMR exome

AF:

0.00234

Gnomad ASJ exome

AF:

0.00260

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0415

Gnomad FIN exome

AF:

0.00944

Gnomad NFE exome

AF:

0.0120

Gnomad OTH exome

AF:

0.0123

GnomAD4 exome

AF:

0.0123

AC:

18023

AN:

1460734

Hom.:

177

Cov.:

AF XY:

0.0131

AC XY:

9526

AN XY:

726646

show subpopulations

Gnomad4 AFR exome

AF:

0.00191

Gnomad4 AMR exome

AF:

0.00304

Gnomad4 ASJ exome

AF:

0.00187

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0378

Gnomad4 FIN exome

AF:

0.0107

Gnomad4 NFE exome

AF:

0.0119

Gnomad4 OTH exome

AF:

0.0116

GnomAD4 genome

AF:

0.00886

AC:

1349

AN:

152282

Hom.:

Cov.:

AF XY:

0.00917

AC XY:

683

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00236

Gnomad4 AMR

AF:

0.00379

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0433

Gnomad4 FIN

AF:

0.00847

Gnomad4 NFE

AF:

0.0122

Gnomad4 OTH

AF:

0.00711

Alfa

AF:

0.0108

Hom.:

Bravo

AF:

0.00778

TwinsUK

AF:

0.0127

AC:

ALSPAC

AF:

0.0138

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.0120

AC:

103

ExAC

AF:

0.0130

AC:

1577

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.00900

EpiControl

AF:

0.00972

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 13, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 09, 2011	Val575Met in exon 15 of OTOF: This variant is not expected to have clinical sign ificance because it has been reported as a neutral change (Varga 2006, Smith 200 8), is present in dbSNP (rs55676840 ? 4 entries), adn has been identified in our laboratory in ~3% of patients. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive nonsyndromic hearing loss 9

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
not provided, no classification provided	literature only	GeneReviews	-	- -

Nonsyndromic genetic hearing loss

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

May 13, 2022

The filtering allele frequency (the lower threshold of the 95% CI of 1269/30610) of the c.1723G>A (p.Val575Met) variant in the OTOF gene is 3.95% for South Asian chromosome in gnomAD v2.1.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;.

Eigen

Benign

0.15

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D

MetaRNN

Benign

0.0078

T;T

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.2

N;N

REVEL

Uncertain

0.38

Sift

Benign

0.28

T;T

Sift4G

Benign

0.13

T;T

Polyphen

0.80

P;.

Vest4

0.45

MPC

0.26

ClinPred

0.077

GERP RS

4.5

Varity_R

0.26

gMVP

0.76

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