rs139954767

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_194248.3(OTOF):c.1630C>T(p.Arg544Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000749 in 1,609,512 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00090 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00073 ( 2 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:1

Conservation

PhyloP100: 4.78

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 -5 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000901 (134/148792) while in subpopulation NFE AF= 0.00174 (116/66596). AF 95% confidence interval is 0.00148. There are 0 homozygotes in gnomad4. There are 67 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.1630C>T	p.Arg544Cys	missense_variant	Exon 15 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_001287489.2 link	c.1630C>T	p.Arg544Cys	missense_variant	Exon 15 of 46		NP_001274418.1	Q9HC10-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 link	c.1630C>T	p.Arg544Cys	missense_variant	Exon 15 of 47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000403946.7 link	c.1630C>T	p.Arg544Cys	missense_variant	Exon 15 of 46	5		ENSP00000385255.3		Q9HC10-5

Frequencies

GnomAD3 genomes

AF:

0.000901

AC:

134

AN:

148666

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000993

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000667

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000201

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00105

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00174

Gnomad OTH

AF:

0.000489

GnomAD3 exomes

AF:

0.000769

AC:

192

AN:

249668

Hom.:

AF XY:

0.000797

AC XY:

108

AN XY:

135522

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.000400

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00134

Gnomad NFE exome

AF:

0.00118

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000734

AC:

1072

AN:

1460720

Hom.:

Cov.:

AF XY:

0.000778

AC XY:

565

AN XY:

726640

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00189

Gnomad4 NFE exome

AF:

0.000789

Gnomad4 OTH exome

AF:

0.000878

GnomAD4 genome

AF:

0.000901

AC:

134

AN:

148792

Hom.:

Cov.:

AF XY:

0.000920

AC XY:

AN XY:

72800

show subpopulations

Gnomad4 AFR

AF:

0.0000990

Gnomad4 AMR

AF:

0.0000666

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000201

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00105

Gnomad4 NFE

AF:

0.00174

Gnomad4 OTH

AF:

0.000484

Alfa

AF:

0.00143

Hom.:

Bravo

AF:

0.000635

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000801

AC:

EpiCase

AF:

0.00115

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 20, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in a patient with hearing loss in published literature (Sommen et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 27068579) -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

OTOF: PP3 -

May 14, 2019

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:2

Aug 21, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg544Cys variant in OTOF has been identified in 1 individual with autosom al recessive sensorineural hearing loss who carried a second OTOF variant of unc ertain significance; it is unclear whether these variants are in trans (Sommen 2 016). The p.Arg544Cys variant has also been identified by our laboratory in 6 in dividuals with hearing loss; however, none of these individuals carried a varian t affecting the other copy of the OTOF gene or was reported to have auditory neu ropathy typically associated with OTOF related hearing loss. This variant has be en reported in ClinVar (Variation ID: 48176). It has been identified in 0.15% (1 93/125430) of European chromosomes by the Genome Aggregation Database (gnomAD, h ttp://gnomad.broadinstitute.org); however, this frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation anal ysis suggest that the p.Arg544Cys variant may impact the protein, though this in formation is not predictive enough to determine pathogenicity. In summary, the c linical significance of the p.Arg544Cys variant is uncertain. ACMG/AMP Criteria applied: PP3, BS1_Supporting. -

Feb 14, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: OTOF c.1630C>T (p.Arg544Cys) results in a non-conservative amino acid change located in the Ferlin, third C2 domain (IPR037722) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00077 in 249668 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 (0.00077 vs 0.0011), allowing no conclusion about variant significance. c.1630C>T has been reported in the literature in individuals affected with Nonsyndromic Hearing Loss without evidence of cosegregation (Kothiyal_2010, Sommen_2016). These reports do not provide unequivocal conclusions about association of the variant with Nonsyndromic Hearing Loss And Deafness, Type 9. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variants as likely benign (n=1) or uncertain significance (n=7). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Autosomal recessive nonsyndromic hearing loss 9

Uncertain:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Feb 16, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hearing impairment

Uncertain:1

Apr 12, 2021

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3_Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

D;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.33

MetaRNN

Uncertain

0.72

D;D

MetaSVM

Uncertain

0.50

MutationAssessor

Pathogenic

3.4

M;M

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-7.6

D;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.95

MVP

0.92

MPC

0.77

ClinPred

0.19

GERP RS

3.2

Varity_R

0.81

gMVP

0.72

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