rs397515596

Variant names:

• chr2-26475982-CGGCAAAGAGGCTGCGGGC-TGCGCTCGGAG
• rs397515596
• NM_194248.3:c.2905_2923delGCCCGCAGCCTCTTTGCCGinsCTCCGAGCGCA

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PS1 PM2 PP5_Moderate

The NM_194248.3(OTOF):​c.2905_2923delGCCCGCAGCCTCTTTGCCGinsCTCCGAGCGCA​(p.Ala969LeufsTer30) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTOF NM_194248.3 frameshift, missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 9.93

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS1: Transcript NM_194248.3 (OTOF) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-26475982-CGGCAAAGAGGCTGCGGGC-TGCGCTCGGAG is Pathogenic according to our data. Variant chr2-26475982-CGGCAAAGAGGCTGCGGGC-TGCGCTCGGAG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65794.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.2905_2923delGCCCGCAGCCTCTTTGCCGinsCTCCGAGCGCA	p.Ala969LeufsTer30	frameshift_variant, missense_variant	Exon 24 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.664_682delGCCCGCAGCCTCTTTGCCGinsCTCCGAGCGCA	p.Ala222LeufsTer30	frameshift_variant, missense_variant	Exon 7 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.2905_2923delGCCCGCAGCCTCTTTGCCGinsCTCCGAGCGCA	p.Ala969LeufsTer30	frameshift_variant, missense_variant	Exon 24 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.664_682delGCCCGCAGCCTCTTTGCCGinsCTCCGAGCGCA	p.Ala222LeufsTer30	frameshift_variant, missense_variant	Exon 7 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bilateral sensorineural hearing impairment Pathogenic:1

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Laboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The c.2905_2923delinsCTCCGAGCGCA was identified in a Brazilian patient with non-syndromic hearing loss, but a second pathogenic variant could not be detected. Thus its clinical significance is unknown -

Autosomal recessive nonsyndromic hearing loss 9 Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515596; hg19: chr2-26698850;