2-26458218-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM2PP3PP5_Very_StrongBS1_Supporting

The NM_194323.3(OTOF):c.3515G>A(p.Arg1172Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000684 in 1,578,266 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000073 ( 1 hom. )

Consequence

OTOF
NM_194323.3 missense, splice_region

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.83

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 Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 2-26458218-C-T is Pathogenic according to our data. Variant chr2-26458218-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 548986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26458218-C-T is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000729 (104/1426078) while in subpopulation EAS AF= 0.00142 (53/37346). AF 95% confidence interval is 0.00111. There are 1 homozygotes in gnomad4_exome. There are 48 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.*20G>A		splice_region_variant	Exon 47 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 link	c.3515G>A	p.Arg1172Gln	missense_variant, splice_region_variant	Exon 29 of 29	ENST00000339598.8	NP_919304.1	Q9HC10-2
OTOF	NM_194248.3 link	c.*20G>A		3_prime_UTR_variant	Exon 47 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOF	ENST00000272371.7 link	c.*20G>A		splice_region_variant	Exon 47 of 47	1	NM_194248.3	ENSP00000272371.2	Q9HC10-1
OTOF	ENST00000339598.8 link	c.3515G>A	p.Arg1172Gln	missense_variant, splice_region_variant	Exon 29 of 29	1	NM_194323.3	ENSP00000344521.3	Q9HC10-2
OTOF	ENST00000272371 link	c.*20G>A		3_prime_UTR_variant	Exon 47 of 47	1	NM_194248.3	ENSP00000272371.2	Q9HC10-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000387

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:

0.0000434

AC:

AN:

184120

Hom.:

AF XY:

0.0000506

AC XY:

AN XY:

98812

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000305

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000523

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000729

AC:

104

AN:

1426078

Hom.:

Cov.:

AF XY:

0.0000680

AC XY:

AN XY:

706214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00142

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000448

Gnomad4 OTH exome

AF:

0.0000338

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000487

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000254

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Jan 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The OTOF gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_194323.2, and corresponds to NM_194248.2:c.*20G>A in the primary transcript. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1172 of the OTOF protein (p.Arg1172Gln). This variant is present in population databases (rs201326023, gnomAD 0.02%). This missense change has been observed in individual(s) with auditory neuropathy spectrum disorder (PMID: 26632695). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.R1939Q. ClinVar contains an entry for this variant (Variation ID: 548986). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Jul 04, 2023

GeneDx

Significance: Pathogenic

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 and a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 35248088, 26346818, 31095577, 26632695, 24053799, 30482216, 24814232, 23562982, 27621663, 16097006, 22906306, 22575033, 14635104, 12525542, 34426522, 34424407) -

Auditory neuropathy spectrum disorder

Pathogenic:1

Oct 20, 2020

Department of Otolaryngology, Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Aug 06, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.*20G>A alteration is located in the 3' untranslated region (3' UTR) of the OTOF gene. This alteration consists of a G to A substitution 20 nucleotides after the last coding exon of the OTOF gene. Report as NM_001287489 c.5816G>A (p.R1939Q) - requires manual report edits Based on data from gnomAD, the A allele has an overall frequency of 0.004% (9/215492) total alleles studied. The highest observed frequency was 0.027% (4/14656) of East Asian alleles. This variant has been identified in the homozygous state and/or in conjunction with other OTOF variants in individuals with hearing loss (Matsunaga, 2012; Chang, 2015; Lee, 2021). Based on the available evidence, this alteration is classified as pathogenic. -

OTOF-related disorder

Pathogenic:1

Oct 04, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The OTOF c.5816G>A variant is predicted to result in the amino acid substitution p.Arg1939Gln. This variant was reported in the homozygous and compound heterozygous states in multiple individuals with auditory neuropathy or nonsyndromic hearing loss (described as c.6141G>A, Varga. 2003. PubMed ID: 12525542; Chang. 2015. PubMed ID: 26632695; Matsunaga. 2012. PubMed ID: 22575033; Table S1, Thorpe. 2021. PubMed ID: 34424407; Mutai. 2022. PubMed ID: 35248088). This variant is reported in 0.027% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-26681086-C-T). This variant is interpreted as pathogenic. -

Autosomal recessive nonsyndromic hearing loss 9

Pathogenic:1

Feb 20, 2018

Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

DANN

Pathogenic

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Uncertain

0.70

PROVEAN

Uncertain

-3.8

D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0020

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.78

MutPred

0.64

Gain of catalytic residue at R1172 (P = 0.0095);.;

MVP

0.96

ClinPred

0.44

GERP RS

4.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.73

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.73

Position offset: -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