rs145239283

Variant names:

Variant summary

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

The NM_194248.3(OTOF):c.3076A>T(p.Arg1026Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000695 in 1,613,156 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 4 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.79

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=0.008550972).

BP6

Variant 2-26475409-T-A is Benign according to our data. Variant chr2-26475409-T-A is described in ClinVar as [Benign]. Clinvar id is 48213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00409 (622/152246) while in subpopulation AFR AF= 0.013 (539/41534). AF 95% confidence interval is 0.0121. There are 6 homozygotes in gnomad4. There are 295 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.3076A>T	p.Arg1026Trp	missense_variant	Exon 25 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 link	c.835A>T	p.Arg279Trp	missense_variant	Exon 8 of 29	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.3076A>T	p.Arg1026Trp	missense_variant	Exon 25 of 47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 link	c.835A>T	p.Arg279Trp	missense_variant	Exon 8 of 29	1	NM_194323.3	ENSP00000344521.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.00410

AC:

623

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00477

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00100

AC:

252

AN:

250748

Hom.:

AF XY:

0.000773

AC XY:

105

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.0120

Gnomad AMR exome

AF:

0.00124

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.000342

AC:

499

AN:

1460910

Hom.:

Cov.:

AF XY:

0.000292

AC XY:

212

AN XY:

726768

show subpopulations

Gnomad4 AFR exome

AF:

0.0107

Gnomad4 AMR exome

AF:

0.00157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.000894

GnomAD4 genome

AF:

0.00409

AC:

622

AN:

152246

Hom.:

Cov.:

AF XY:

0.00396

AC XY:

295

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0130

Gnomad4 AMR

AF:

0.00477

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00114

Hom.:

Bravo

AF:

0.00463

ESP6500AA

AF:

0.0118

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00128

AC:

155

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 19, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

Sep 25, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arg1026Trp in exon 25 of OTOF: This variant is not expected to have clinical sig nificance because it has been identified in dbSNP in 0.4% (18/4544) of control c hromosomes (rs145239283). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

.;.;.;D;.;.

Eigen

Benign

0.079

Eigen_PC

Benign

-0.019

FATHMM_MKL

Uncertain

0.81

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

MetaRNN

Benign

0.0086

T;T;T;T;T;T

MetaSVM

Uncertain

0.085

MutationAssessor

Uncertain

2.4

.;.;.;M;M;.

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.0

D;D;.;D;D;.

REVEL

Uncertain

0.59

Sift

Uncertain

0.0060

D;D;.;D;D;.

Sift4G

Uncertain

0.011

D;D;.;D;D;.

Polyphen

1.0

D;D;.;D;.;D

Vest4

0.74

MVP

0.93

MPC

0.67

ClinPred

0.036

GERP RS

2.8

Varity_R

0.45

gMVP

0.64

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