NM_001378609.3:c.841_842delAT
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001378609.3(OTOGL):c.841_842delAT(p.Met281ValfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000269 in 1,559,118 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001378609.3 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
OTOGL | NM_001378609.3 | c.841_842delAT | p.Met281ValfsTer4 | frameshift_variant | Exon 10 of 59 | ENST00000547103.7 | NP_001365538.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OTOGL | ENST00000547103.7 | c.841_842delAT | p.Met281ValfsTer4 | frameshift_variant | Exon 10 of 59 | 5 | NM_001378609.3 | ENSP00000447211.2 | ||
OTOGL | ENST00000646859.1 | c.841_842delAT | p.Met281ValfsTer4 | frameshift_variant | Exon 15 of 63 | ENSP00000496036.1 | ||||
OTOGL | ENST00000643417.1 | n.1501_1502delAT | non_coding_transcript_exon_variant | Exon 13 of 23 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 151950Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000284 AC: 5AN: 176338Hom.: 0 AF XY: 0.0000317 AC XY: 3AN XY: 94714
GnomAD4 exome AF: 0.0000263 AC: 37AN: 1407168Hom.: 0 AF XY: 0.0000172 AC XY: 12AN XY: 696284
GnomAD4 genome AF: 0.0000329 AC: 5AN: 151950Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74184
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 84B Pathogenic:2
- -
- -
not provided Pathogenic:1
This sequence change creates a premature translational stop signal (p.Met272Valfs*4) in the OTOGL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOGL are known to be pathogenic (PMID: 23122586). This variant is present in population databases (rs776663993, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with OTOGL-related conditions. ClinVar contains an entry for this variant (Variation ID: 228285). For these reasons, this variant has been classified as Pathogenic. -
Rare genetic deafness Pathogenic:1
The p.Met272ValfsX4 variant in OTOGL has not been previously reported in individ uals with hearing loss, but has been identified in 2/12820 chromosomes by the Ex ome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 272 and leads to a premature termination codon 4 amino acids downstream . This alteration is then predicted to lead to a truncated or absent protein. I n summary, although additional studies are required to fully establish its clini cal significance, this variant is likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at