2-26516560-C-T

Position:

chr2-26516560-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_194248.3(OTOF):c.367G>A(p.Gly123Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 1,610,560 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 21 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.05

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=0.007595271).

BP6

Variant 2-26516560-C-T is Benign according to our data. Variant chr2-26516560-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 48222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26516560-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00279 (4075/1458292) while in subpopulation MID AF= 0.0153 (88/5768). AF 95% confidence interval is 0.0127. There are 21 homozygotes in gnomad4_exome. There are 2207 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.367G>A	p.Gly123Ser	missense_variant	5/47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_001287489.2 linkuse as main transcript	c.367G>A	p.Gly123Ser	missense_variant	5/46		NP_001274418.1	Q9HC10-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.367G>A	p.Gly123Ser	missense_variant	5/47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000403946.7 linkuse as main transcript	c.367G>A	p.Gly123Ser	missense_variant	5/46	5		ENSP00000385255.3		Q9HC10-5

Frequencies

GnomAD3 genomes

AF:

0.00195

AC:

296

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.0219

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00705

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00223

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00342

AC:

852

AN:

248832

Hom.:

AF XY:

0.00378

AC XY:

509

AN XY:

134788

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00231

Gnomad ASJ exome

AF:

0.0212

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00676

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00277

Gnomad OTH exome

AF:

0.00524

GnomAD4 exome

AF:

0.00279

AC:

4075

AN:

1458292

Hom.:

Cov.:

AF XY:

0.00304

AC XY:

2207

AN XY:

725678

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.00201

Gnomad4 ASJ exome

AF:

0.0197

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00721

Gnomad4 FIN exome

AF:

0.000160

Gnomad4 NFE exome

AF:

0.00226

Gnomad4 OTH exome

AF:

0.00378

GnomAD4 genome

AF:

0.00194

AC:

295

AN:

152268

Hom.:

Cov.:

AF XY:

0.00175

AC XY:

130

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.0219

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00706

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00224

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00297

Hom.:

Bravo

AF:

0.00208

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00395

AC:

ExAC

AF:

0.00318

AC:

386

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00311

EpiControl

AF:

0.00320

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2019	This variant is associated with the following publications: (PMID: 26969326, 29484972, 31095577) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	OTOF: BP4, BS2 -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2022	Variant summary: OTOF c.367G>A (p.Gly123Ser) results in a non-conservative amino acid change located in the Ferlin, first C2 domain (IPR037726) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0034 in 248832 control chromosomes (gnomAD), including 4 homozygotes. The variant occurs predominantly at a frequency of 0.0068 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 6-fold of the estimated maximal expected allele frequency for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Six ClinVar submitters have assessed the variant since 2014: four classified the variant as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 15, 2012	Gly123Ser in Exon 05A of OTOF: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% (34/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs116314622). -

OTOF-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 24, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal recessive nonsyndromic hearing loss 9

Benign:1

Benign, criteria provided, single submitter

clinical testing

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Nov 03, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

T;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.0076

T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

0.34

N;N

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.28

Sift

Benign

0.064

T;T

Sift4G

Uncertain

0.012

D;D

Polyphen

0.24

B;.

Vest4

0.46

MVP

0.85

MPC

0.18

ClinPred

0.017

GERP RS

4.8

Varity_R

0.15

gMVP

0.44

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