rs397515596

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 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 (★). Variant results in nonsense mediated mRNA decay. The gene OTOF is included in the ClinGen Criteria Specification Registry.

• 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
• Publications: 2 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, Unknown Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for OTOF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 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 2-26475982-CGGCAAAGAGGCTGCGGGC-TGCGCTCGGAG is Pathogenic according to our data. Variant chr2-26475982-CGGCAAAGAGGCTGCGGGC-TGCGCTCGGAG is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 65794.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194248.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	NM_194248.3	MANE Select	c.2905_2923delGCCCGCAGCCTCTTTGCCGinsCTCCGAGCGCA	p.Ala969LeufsTer30	frameshift missense	Exon 24 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.664_682delGCCCGCAGCCTCTTTGCCGinsCTCCGAGCGCA	p.Ala222LeufsTer30	frameshift missense	Exon 7 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.2905_2923delGCCCGCAGCCTCTTTGCCGinsCTCCGAGCGCA	p.Ala969LeufsTer30	frameshift missense	Exon 24 of 46	NP_001274418.1	Q9HC10-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.2905_2923delGCCCGCAGCCTCTTTGCCGinsCTCCGAGCGCA	p.Ala969LeufsTer30	frameshift missense	Exon 24 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.664_682delGCCCGCAGCCTCTTTGCCGinsCTCCGAGCGCA	p.Ala222LeufsTer30	frameshift missense	Exon 7 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.664_682delGCCCGCAGCCTCTTTGCCGinsCTCCGAGCGCA	p.Ala222LeufsTer30	frameshift missense	Exon 6 of 29	ENSP00000383906.4	A0A2U3TZT7

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

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Bilateral sensorineural hearing impairment (1)
-	-	-	Autosomal recessive nonsyndromic hearing loss 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs397515596; hg19: chr2-26698850;