2-26474554-C-G

Position:

chr2-26474554-C-G

Variant summary

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

The NM_194248.3(OTOF):c.3247G>C(p.Ala1083Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,612,842 control chromosomes in the GnomAD database, including 374 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 20 hom., cov: 31)

Exomes 𝑓: 0.019 ( 354 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 0.494

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=0.005121857).

BP6

Variant 2-26474554-C-G is Benign according to our data. Variant chr2-26474554-C-G is described in ClinVar as [Benign]. Clinvar id is 21844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26474554-C-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0147 (2245/152340) while in subpopulation NFE AF= 0.0195 (1329/68028). AF 95% confidence interval is 0.0187. There are 20 homozygotes in gnomad4. There are 1020 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.3247G>C	p.Ala1083Pro	missense_variant	26/47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 linkuse as main transcript	c.1006G>C	p.Ala336Pro	missense_variant	9/29	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.3247G>C	p.Ala1083Pro	missense_variant	26/47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 linkuse as main transcript	c.1006G>C	p.Ala336Pro	missense_variant	9/29	1	NM_194323.3	ENSP00000344521.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.0147

AC:

2243

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00921

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0124

Gnomad ASJ

AF:

0.0231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0200

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0195

Gnomad OTH

AF:

0.0120

GnomAD3 exomes

AF:

0.0145

AC:

3606

AN:

249378

Hom.:

AF XY:

0.0147

AC XY:

1988

AN XY:

135310

show subpopulations

Gnomad AFR exome

AF:

0.00949

Gnomad AMR exome

AF:

0.00740

Gnomad ASJ exome

AF:

0.0218

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00301

Gnomad FIN exome

AF:

0.0221

Gnomad NFE exome

AF:

0.0206

Gnomad OTH exome

AF:

0.0156

GnomAD4 exome

AF:

0.0195

AC:

28469

AN:

1460502

Hom.:

354

Cov.:

AF XY:

0.0190

AC XY:

13770

AN XY:

726540

show subpopulations

Gnomad4 AFR exome

AF:

0.00884

Gnomad4 AMR exome

AF:

0.00786

Gnomad4 ASJ exome

AF:

0.0206

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00321

Gnomad4 FIN exome

AF:

0.0228

Gnomad4 NFE exome

AF:

0.0222

Gnomad4 OTH exome

AF:

0.0168

GnomAD4 genome

AF:

0.0147

AC:

2245

AN:

152340

Hom.:

Cov.:

AF XY:

0.0137

AC XY:

1020

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00926

Gnomad4 AMR

AF:

0.0123

Gnomad4 ASJ

AF:

0.0231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.0200

Gnomad4 NFE

AF:

0.0195

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.00863

Hom.:

Bravo

AF:

0.0143

TwinsUK

AF:

0.0251

AC:

ALSPAC

AF:

0.0202

AC:

ESP6500AA

AF:

0.0104

AC:

ESP6500EA

AF:

0.0233

AC:

200

ExAC

AF:

0.0143

AC:

1735

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0222

EpiControl

AF:

0.0210

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2018	This variant is associated with the following publications: (PMID: 16371502, 18381613, 20301429) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 06, 2010

Ala1083Pro in exon 26 of OTOF: This variant is not expected to have clinical sig nificance because this residue is not highly conserved across species and this v ariant has been reported as benign in two publications (Varga 2006, Rodriguez-Ba llesteros 2008). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

.;.;.;T;.;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.34

LIST_S2

Uncertain

0.91

D;D;D;D;D;D

MetaRNN

Benign

0.0051

T;T;T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.81

.;.;.;L;L;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.9

N;N;.;N;N;.

REVEL

Benign

0.045

Sift

Benign

0.27

T;T;.;T;T;.

Sift4G

Benign

0.27

T;T;.;T;T;.

Polyphen

0.28

B;P;.;P;.;P

Vest4

0.29

MPC

0.31

ClinPred

0.0060

GERP RS

4.9

Varity_R

0.25

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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