chr2-26475913-C-T
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_194248.3(OTOF):c.2991+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000551 in 1,452,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_194248.3 splice_donor, intron
Scores
Clinical Significance
Conservation
Publications
- autosomal recessive nonsyndromic hearing loss 9Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
- hearing loss, autosomal recessiveInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
OTOF | NM_194248.3 | c.2991+1G>A | splice_donor_variant, intron_variant | Intron 24 of 46 | ENST00000272371.7 | NP_919224.1 | ||
OTOF | NM_194323.3 | c.750+1G>A | splice_donor_variant, intron_variant | Intron 7 of 28 | ENST00000339598.8 | NP_919304.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.2991+1G>A | splice_donor_variant, intron_variant | Intron 24 of 46 | 1 | NM_194248.3 | ENSP00000272371.2 | |||
OTOF | ENST00000339598.8 | c.750+1G>A | splice_donor_variant, intron_variant | Intron 7 of 28 | 1 | NM_194323.3 | ENSP00000344521.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD2 exomes AF: 0.0000128 AC: 3AN: 235052 AF XY: 0.00000784 show subpopulations
GnomAD4 exome AF: 0.00000551 AC: 8AN: 1452204Hom.: 0 Cov.: 33 AF XY: 0.00000693 AC XY: 5AN XY: 721584 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
OTOF-related disorder Pathogenic:1
The OTOF c.2991+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0028% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in OTOF are expected to be pathogenic. This variant is interpreted as likely pathogenic. -
not provided Pathogenic:1
Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 21841). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects a donor splice site in intron 24 of the OTOF gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in OTOF are known to be pathogenic (PMID: 18381613, 19250381, 22575033). This variant has not been reported in the literature in individuals affected with OTOF-related conditions. -
Autosomal recessive nonsyndromic hearing loss 9 Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at