2-26464907-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_194248.3(OTOF):c.4922G>A(p.Arg1641His) variant causes a missense change. The variant allele was found at a frequency of 0.0000482 in 1,597,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 4.14

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03976506).

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000477 (69/1445212) while in subpopulation AMR AF= 0.00124 (54/43424). AF 95% confidence interval is 0.000979. There are 0 homozygotes in gnomad4_exome. There are 27 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.4922G>A	p.Arg1641His	missense_variant	Exon 39 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 link	c.2621G>A	p.Arg874His	missense_variant	Exon 22 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.4922G>A	p.Arg1641His	missense_variant	Exon 39 of 47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 link	c.2621G>A	p.Arg874His	missense_variant	Exon 22 of 29	1	NM_194323.3	ENSP00000344521.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000203

AC:

AN:

240798

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

130274

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00149

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000906

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000477

AC:

AN:

1445212

Hom.:

Cov.:

AF XY:

0.0000376

AC XY:

AN XY:

718118

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00124

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000136

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000174

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.000181

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Jun 25, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Feb 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Apr 04, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Arg1641His vari ant in OTOF has been previously identified two Hispanic individuals with hearing loss and one affected sibling by our laboratory However, none of these individu als carried a second variant in the OTOF gene. In addition, the Arg1641His varia nt been identified in 0.8% (1/128) of Mexican chromosomes by the 1000Genomes pro ject (dbSNP rs200283244). Computational prediction tools and conservation analys es suggest that the Arg1641His variant may not impact the protein, though this i nformation is not predictive enough to rule out pathogenicity. Of note, two mamm als, walrus and panda, also carry a histidine (His) at this position. In summary , the clinical significance of this variant cannot be determined with certainty; however, based upon the absence of a second OTOF variant in affected individual s, its presence in the general population, and the lack of conservation at the A rg1641 position, we would lean towards a more likely benign role. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Uncertain

0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

.;.;.;T;.;.

Eigen

Benign

0.081

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.82

T;T;D;D;D;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.040

T;T;T;T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.2

.;.;.;M;M;.

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.6

D;D;.;D;D;.

REVEL

Benign

0.26

Sift

Benign

0.049

D;D;.;T;T;.

Sift4G

Uncertain

0.035

D;T;.;D;D;.

Polyphen

0.53

P;B;.;B;.;B

Vest4

0.38

MVP

0.86

MPC

0.20

ClinPred

0.18

GERP RS

4.9

Varity_R

0.21

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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