rs111033342
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_194248.3(OTOF):c.4228-1G>T variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000889 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
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
OTOF | NM_194248.3 | c.4228-1G>T | splice_acceptor_variant, intron_variant | Intron 34 of 46 | ENST00000272371.7 | NP_919224.1 | ||
OTOF | NM_194323.3 | c.1927-1G>T | 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>T | splice_acceptor_variant, intron_variant | Intron 34 of 46 | 1 | NM_194248.3 | ENSP00000272371.2 | |||
OTOF | ENST00000339598.8 | c.1927-1G>T | 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: 0.0000147 AC XY: 2AN XY: 135898
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461868Hom.: 0 Cov.: 35 AF XY: 0.0000110 AC XY: 8AN XY: 727236
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Nonsyndromic genetic hearing loss Pathogenic:1
Variant summary: OTOF c.4228-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251458 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4228-1G>T in individuals affected with Nonsyndromic Hearing Loss And Deafness, Type 9 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at