11-17629271-G-A
Variant summary
Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_001292063.2(OTOG):c.6667G>A(p.Val2223Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,550,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V2223V) has been classified as Likely benign.
Frequency
Consequence
NM_001292063.2 missense
Scores
Clinical Significance
Conservation
Publications
- autosomal recessive nonsyndromic hearing loss 18BInheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics
- nonsyndromic genetic hearing lossInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- hearing loss, autosomal recessiveInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_benign. The variant received -5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OTOG | ENST00000399397.6 | c.6667G>A | p.Val2223Met | missense_variant | Exon 40 of 56 | 5 | NM_001292063.2 | ENSP00000382329.2 | ||
OTOG | ENST00000399391.7 | c.6703G>A | p.Val2235Met | missense_variant | Exon 39 of 55 | 5 | ENSP00000382323.2 | |||
OTOG | ENST00000342528.2 | n.4005G>A | non_coding_transcript_exon_variant | Exon 16 of 22 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152242Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.000357 AC: 53AN: 148440 AF XY: 0.000275 show subpopulations
GnomAD4 exome AF: 0.0000622 AC: 87AN: 1398220Hom.: 0 Cov.: 31 AF XY: 0.0000493 AC XY: 34AN XY: 689628 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000656 AC: 10AN: 152360Hom.: 0 Cov.: 33 AF XY: 0.0000805 AC XY: 6AN XY: 74504 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:2
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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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 227790). This variant has not been reported in the literature in individuals affected with OTOG-related conditions. This variant is present in population databases (rs572886375, gnomAD 0.2%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2235 of the OTOG protein (p.Val2235Met). -
not specified Benign:1
p.Val2235Met in exon 39 of OTOG: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, 5 mammals (orangutan, rhesus, crab-eating macaque, baboon and green monkey ) have a methionine (Met) at this position despite high nearby amino acid conser vation. In addition, computational prediction tools do not suggest a high likeli hood of impact to the protein. -
OTOG-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at