rs142111099

Positions:

chr2-26461855-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2_SupportingPM5PM3PP3PP4

This summary comes from the ClinGen Evidence Repository: The c.5374C>T variant in OTOF is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 1792. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006152 (1/16256 alleles) in the African/African American population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.843, which is above the threshold of 0.7, evidence that correlates with impact to OTOF function (PP3). 1 different missense variant, c.5375G>A (p.R1792H) (PMID:29048421, ClinVar Variation ID: 48259), in the same codon has been classified as likely pathogenic for nonsyndromic hearing loss by multiple submitters in ClinVar (PM5). This variant has been detected in at least 3 individuals with AR deafness. For two of those individuals, both were compound heterozygous for the variant and a VUS meeting PM2_Supporting, and both of those were confirmed in trans by family testing (c.2676G>A (p.K892K) which occurs at the last nucleotide in exon (22) of OTOF and c.4748G>A (p.R1583H), 1.5 PM3 points, PMID:34416374, Universitätsmedizin Göttingen, Institute of Human Genetics/Institute of Auditory Neuroscience & InnerEarLab) (PM3). At least one patient was compound heterozygous for this variant and the p.K892K variant displayed auditory neuropathy spectrum disorder (ANSD), which is highly specific for autosomal recessive deafness (PP4, PMID:34416374). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PP3, PP4, PM3, PM5 (ClinGen Hearing Loss VCEP specifications version 2; 6/27/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA182451/MONDO:0019497/023

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

OTOF
NM_194248.3 missense

Scores

15

3

1

Clinical Significance

Likely pathogenic reviewed by expert panel P:2U:1

Conservation

PhyloP100: 6.70

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_pathogenic. Variant got 7 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PM5

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.5374C>T	p.Arg1792Cys	missense_variant	43/47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 linkuse as main transcript	c.3073C>T	p.Arg1025Cys	missense_variant	26/29	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.5374C>T	p.Arg1792Cys	missense_variant	43/47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 linkuse as main transcript	c.3073C>T	p.Arg1025Cys	missense_variant	26/29	1	NM_194323.3	ENSP00000344521.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

2

AN:

152172

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

2

AN:

251482

Hom.:

0

AF XY:

0.00000736

AC XY:

1

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

14

AN:

1461890

Hom.:

0

Cov.:

33

AF XY:

0.0000110

AC XY:

8

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

2

AN:

152172

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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:

0.00

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.000227

AC:

1

ESP6500EA

AF:

0.00

AC:

0

ExAC

AF:

0.0000247

AC:

3

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Nonsyndromic genetic hearing loss

Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Jun 29, 2023

The c.5374C>T variant in OTOF is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 1792. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006152 (1/16256 alleles) in the African/African American population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.843, which is above the threshold of 0.7, evidence that correlates with impact to OTOF function (PP3). 1 different missense variant, c.5375G>A (p.R1792H) (PMID: 29048421, ClinVar Variation ID: 48259), in the same codon has been classified as likely pathogenic for nonsyndromic hearing loss by multiple submitters in ClinVar (PM5). This variant has been detected in at least 3 individuals with AR deafness. For two of those individuals, both were compound heterozygous for the variant and a VUS meeting PM2_Supporting, and both of those were confirmed in trans by family testing (c.2676G>A (p.K892K) which occurs at the last nucleotide in exon (22) of OTOF and c.4748G>A (p.R1583H), 1.5 PM3 points, PMID: 34416374, Universitätsmedizin Göttingen, Institute of Human Genetics/Institute of Auditory Neuroscience & InnerEarLab) (PM3). At least one patient was compound heterozygous for this variant and the p.K892K variant displayed auditory neuropathy spectrum disorder (ANSD), which is highly specific for autosomal recessive deafness (PP4, PMID: 34416374). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PP3, PP4, PM3, PM5 (ClinGen Hearing Loss VCEP specifications version 2; 6/27/2022). -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1792 of the OTOF protein (p.Arg1792Cys). This variant is present in population databases (rs142111099, gnomAD 0.007%). This missense change has been observed in individuals with OTOF-related conditions (PMID: 31095577, 34416374, 34536124; Invitae). ClinVar contains an entry for this variant (Variation ID: 178503). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt OTOF protein function with a positive predictive value of 80%. This variant disrupts the p.Arg1792 amino acid residue in OTOF. Other variant(s) that disrupt this residue have been observed in individuals with OTOF-related conditions (PMID: 29048421), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 15, 2016

proposed classification - variant undergoing re-assessment, contact laboratory -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.32

D

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

32

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.80

.;.;.;D;.;.

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.91

D

LIST_S2

Uncertain

0.97

D;D;D;D;D;D

M_CAP

Pathogenic

0.35

D

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D

MetaSVM

Pathogenic

0.83

D

MutationAssessor

Pathogenic

3.4

.;.;.;M;M;.

PrimateAI

Pathogenic

0.90

D

PROVEAN

Pathogenic

-7.8

D;D;D;D;D;.

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;D;D;D;D;.

Sift4G

Pathogenic

0.0

D;D;.;D;D;.

Polyphen

1.0

D;D;.;D;.;D

Vest4

0.93

MVP

0.94

MPC

0.70

ClinPred

1.0

D

GERP RS

4.1

Varity_R

0.88

gMVP

0.90

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.

Other links and lift over

dbSNP: rs142111099; hg19: chr2-26684723; COSMIC: COSV55507957; COSMIC: COSV55507957;