rs80356600

Positions:

• chr2-26466723-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_194248.3(OTOF):​c.4491T>A​(p.Tyr1497Ter) 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, single submitter P:2 O:1
• Conservation: PhyloP100: 0.243

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 12 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 id is 6133.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-26466723-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.4491T>A	p.Tyr1497Ter	stop_gained	36/47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.2190T>A	p.Tyr730Ter	stop_gained	19/29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.4491T>A	p.Tyr1497Ter	stop_gained	36/47	1	NM_194248.3	ENSP00000272371	A1
OTOF	ENST00000339598.8	c.2190T>A	p.Tyr730Ter	stop_gained	19/29	1	NM_194323.3	ENSP00000344521

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1999	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 26, 2015

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
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.88
GERP RS		-2.6

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

Publications

LitVar

Other links and lift over

dbSNP: rs80356600; hg19: chr2-26689591;