chr2-26477725-C-A

Variant names:

• chr2-26477725-C-A
• rs397515591
• NM_194248.3:c.2239G>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_194248.3(OTOF):​c.2239G>T​(p.Glu747*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000205 in 1,460,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: OTOF NM_194248.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 4.04

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-26477725-C-A is Pathogenic according to our data. Variant chr2-26477725-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 65787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26477725-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.2239G>T	p.Glu747*	stop_gained	Exon 19 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.-3G>T		5_prime_UTR_variant	Exon 2 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.2239G>T	p.Glu747*	stop_gained	Exon 19 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.-3G>T		5_prime_UTR_variant	Exon 2 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249840 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135638

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460440 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726502

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 9 Pathogenic:3 Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jun 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2020

King Laboratory, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

OTOF c.2239G>T, p.E747* is homozygous in 2 children with profound pre-lingual hearing loss in a Palestinian family (Abu Rayyan 2020). It is absent from 1300 Palestinian controls and present in 1/249840 allele on gnomAD, as a heterozygote -

not provided Pathogenic:2

Feb 09, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 26188103, 18381613, 27766948, 29048421, 34194829, 32747562) -

Sep 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 65787). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with OTOF-related conditions (PMID: 18381613, 27766948). This variant is present in population databases (rs397515591, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Glu747*) in the OTOF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOF are known to be pathogenic (PMID: 18381613, 19250381, 22575033). -

OTOF-related disorder Pathogenic:1

Feb 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The OTOF c.2239G>T variant is predicted to result in premature protein termination (p.Glu747*). This variant has been reported as causative for autosomal recessive nonsyndromic hearing loss (Rodriguez-Ballesteros et al. 2008. PubMed ID: 18381613; Santarelli et al. 2015. PubMed ID: 26188103; Dallol et al. 2016. PubMed ID: 27766948; described as c.169G>T p.Glu57* in Almontashiri et al. 2018. PubMed ID: 29048421). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in OTOF are expected to be pathogenic. This variant is interpreted as pathogenic. -

Rare genetic deafness Pathogenic:1

May 04, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu747X variant in OTOF has been reported in the homozygous state in four individuals with hearing loss, including 1 individual with auditory neuropathy b ased on the presence of otoacoustic emissions (Rodriguez-Ballesteros 2008 and LM M data). This variant has been identified in 1/33574 Latino chromosomes by the G enome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs39 7515591); however, this frequency is low enough to be consistent with a recessiv e carrier frequency for hearing loss. This nonsense variant leads to a prematur e termination codon at position 747, which is predicted to lead to a truncated o r absent protein. In summary, this variant meets criteria to be classified as pa thogenic for autosomal recessive auditory neuropathy spectrum disorder, based on the predicted impact to the protein, reported homozygosity in multiple affected individuals with consistent specific phenotypes, and the low frequency in the g eneral population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.89
GERP RS		4.8

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

Other links and lift over

dbSNP: rs397515591; hg19: chr2-26700593;