NM_194248.3:c.4228-1G>A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_194248.3(OTOF):c.4228-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000308 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. 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_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
OTOF | NM_194248.3 | c.4228-1G>A | splice_acceptor_variant, intron_variant | Intron 34 of 46 | ENST00000272371.7 | NP_919224.1 | ||
OTOF | NM_194323.3 | c.1927-1G>A | splice_acceptor_variant, intron_variant | Intron 17 of 28 | ENST00000339598.8 | NP_919304.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.4228-1G>A | splice_acceptor_variant, intron_variant | Intron 34 of 46 | 1 | NM_194248.3 | ENSP00000272371.2 | |||
OTOF | ENST00000339598.8 | c.1927-1G>A | splice_acceptor_variant, intron_variant | Intron 17 of 28 | 1 | NM_194323.3 | ENSP00000344521.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251458Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135898
GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461868Hom.: 0 Cov.: 35 AF XY: 0.0000344 AC XY: 25AN XY: 727236
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
This sequence change affects an acceptor splice site in intron 34 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 is present in population databases (rs111033342, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with OTOF-related conditions. ClinVar contains an entry for this variant (Variation ID: 48231). 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. -
Rare genetic deafness Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at