2-26466723-A-T

Variant names:

• chr2-26466723-A-T
• rs80356600
• NM_194248.3:c.4491T>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_194248.3(OTOF):​c.4491T>A​(p.Tyr1497*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: OTOF NM_194248.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 0.243
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 2-26466723-A-T is Pathogenic according to our data. Variant chr2-26466723-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 6133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.4491T>A	p.Tyr1497*	stop_gained	Exon 36 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.2190T>A	p.Tyr730*	stop_gained	Exon 19 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.4491T>A	p.Tyr1497*	stop_gained	Exon 36 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.2190T>A	p.Tyr730*	stop_gained	Exon 19 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nonsyndromic genetic hearing loss Pathogenic:1

Nov 08, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: OTOF c.4491T>A (p.Tyr1497X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251450 control chromosomes. c.4491T>A has been reported in the literature in multiple homozygous individuals affected with Nonsyndromic Hearing Loss And Deafness, Type 9 (Yasunaga_1999, Rodrguez-Ballesteros_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18381613, 10192385). ClinVar contains an entry for this variant (Variation ID: 6133). Based on the evidence outlined above, the variant was classified as pathogenic. -

Rare genetic deafness Pathogenic:1

Feb 26, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Tyr1497X variant in OTOF has been reported in 5 Lebanese individuals with hearing loss and segregated with disease in 17 affected relatives from 4 familie s (Yasunaga 1999, Rodriguez-Ballesteros 2008). All individuals were homozygous a nd 1 individual was reported to have auditory neuropathy. The p.Tyr1497X variant has not been identified in large population studies. This nonsense variant lead s to a premature termination codon at position 1497, which is predicted to lead to a truncated or absent protein. In summary, the p.Tyr1497X variant meets our c riteria to be classified as pathogenic for hearing loss in an autosomal recessiv e manner (http://www.partners.org/personalizedmedicine/LMM) based upon the predi cted impact on the protein, segregation studies, and low frequency in the genera l population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.048
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		0.24
Vest4		0.88
GERP RS		-2.6
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80356600; hg19: chr2-26689591;