rs1553356452

Variant names:

• chr2-26494937-C-G
• NM_194248.3:c.897+5G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-26494937-C-G
• chr2-26494937-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_194248.3(OTOF):​c.897+5G>C variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTOF NM_194248.3 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.48

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-26494937-C-G is Pathogenic according to our data. Variant chr2-26494937-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2445638.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.897+5G>C		splice_region_variant, intron_variant	Intron 9 of 46	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2	c.897+5G>C		splice_region_variant, intron_variant	Intron 9 of 45		NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.897+5G>C		splice_region_variant, intron_variant	Intron 9 of 46	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000403946.7	c.897+5G>C		splice_region_variant, intron_variant	Intron 9 of 45	5		ENSP00000385255.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tricho-oculo-dermo-vertebral syndrome Pathogenic:1

Feb 28, 2023

King Laboratory, University of Washington

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This variant occurred in compound heterozygosity with another OTOF splice variant in an individual with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). This patient does not have a diagnosis of Auditory Neuropathy Spectrum Disorder (ANSD). This patient's family has no other history of hearing loss. This variant is a single base pair substitution that is predicted to alter splicing. At the donor splice of OTOF exon 9, the sequence change is GAG gtcagt > GAGgtcact, NNSPLICE is 0.98 and 0.13 and MaxEnt is 7.70 and 2.10 for wildtype and mutant sequences, respectively. In OTOF intron 9, a cryptic splice donor is predicted at chr2:26,717,872 (c.835) with sequence GAG gtgggt, NNSPLICE 0.73 and MaxEnt 7.07. Potential consequences of altered splicing are (a) skipping of OTOF exon 9 resulting in a 132bp message deletion and deletion of 44 amino acids (residues 256-299) within OTOF’s second C2 domain, and (b) cryptic donor splice in OTOF exon 9 resulting in a 63bp message deletion and deletion of 21 amino acids (residues 279-299) within OTOF’s second C2 domain. As of January 2023, this variant has been reported previously in an individual with hearing loss (DFNB9) and is currently classified as pathogenic to ClinVar, and it is not found in any individual on gnomAD. Based on the prediction that this variant leads to a splicing error and a truncated protein, previous classification as pathogenic, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.78		Position offset: 5

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-26717805;