rs374368341
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001378609.3(OTOGL):c.3434C>T(p.Ala1145Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000749 in 1,575,004 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001378609.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
OTOGL | NM_001378609.3 | c.3434C>T | p.Ala1145Val | missense_variant | Exon 30 of 59 | ENST00000547103.7 | NP_001365538.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OTOGL | ENST00000547103.7 | c.3434C>T | p.Ala1145Val | missense_variant | Exon 30 of 59 | 5 | NM_001378609.3 | ENSP00000447211.2 | ||
OTOGL | ENST00000646859.1 | c.3299C>T | p.Ala1100Val | missense_variant | Exon 34 of 63 | ENSP00000496036.1 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152172Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000640 AC: 15AN: 234248Hom.: 0 AF XY: 0.0000625 AC XY: 8AN XY: 128050
GnomAD4 exome AF: 0.0000766 AC: 109AN: 1422714Hom.: 0 Cov.: 30 AF XY: 0.0000662 AC XY: 47AN XY: 709536
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152290Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4AN XY: 74462
ClinVar
Submissions by phenotype
not specified Uncertain:1
The p.Ala1136Val variant in OTOGL has been identified by our laboratory in 1 ind ividual with hearing loss, but the variant did not segregate with disease in an affected sibling. It has also been identified in 3/64954 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s374368341). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational predic tion tools and conservation analyses do not provide strong support for or agains t an impact to the protein. In summary, the clinical significance of the p.Ala11 36Val variant is uncertain. -
Inborn genetic diseases Uncertain:1
The c.3407C>T (p.A1136V) alteration is located in exon 29 (coding exon 29) of the OTOGL gene. This alteration results from a C to T substitution at nucleotide position 3407, causing the alanine (A) at amino acid position 1136 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1136 of the OTOGL protein (p.Ala1136Val). This variant is present in population databases (rs374368341, gnomAD 0.03%). 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: 504848). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Autosomal recessive nonsyndromic hearing loss 84B Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at