rs377611164
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001378609.3(OTOGL):c.518C>T(p.Ser173Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000182 in 1,597,236 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S173S) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )
Consequence
OTOGL
NM_001378609.3 missense
NM_001378609.3 missense
Scores
2
8
2
Clinical Significance
Conservation
PhyloP100: 5.97
Genes affected
OTOGL (HGNC:26901): (otogelin like) The protein encoded by this gene belongs to the otogelin family. This gene is expressed in the inner ear of vertebrates with the highest level of expression seen at the embryonic stage and lowest in adult. Knockdown studies in zebrafish suggest that this gene is essential for normal inner ear function. Mutations in this gene are associated with autosomal recessive deafness. [provided by RefSeq, Dec 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOGL | NM_001378609.3 | c.518C>T | p.Ser173Leu | missense_variant | 8/59 | ENST00000547103.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOGL | ENST00000547103.7 | c.518C>T | p.Ser173Leu | missense_variant | 8/59 | 5 | NM_001378609.3 | P1 | |
OTOGL | ENST00000646859.1 | c.518C>T | p.Ser173Leu | missense_variant | 13/63 | ||||
OTOGL | ENST00000643417.1 | n.1178C>T | non_coding_transcript_exon_variant | 11/23 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152000Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000384 AC: 9AN: 234276Hom.: 0 AF XY: 0.0000391 AC XY: 5AN XY: 128028
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GnomAD4 exome AF: 0.0000173 AC: 25AN: 1445236Hom.: 0 Cov.: 30 AF XY: 0.0000264 AC XY: 19AN XY: 719434
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152000Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74218
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 16, 2017 | The p.Ser164Leu variant in OTOGL has not been previously reported in individuals with hearing loss, but it has been identified in 4/30742 South Asian chromosome s by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs377611164). Although this variant has been seen in the general populatio n, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Ser164Leu variant is uncertain. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 03, 2024 | The c.491C>T (p.S164L) alteration is located in exon 7 (coding exon 7) of the OTOGL gene. This alteration results from a C to T substitution at nucleotide position 491, causing the serine (S) at amino acid position 164 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 06, 2021 | 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with OTOGL-related conditions. ClinVar contains an entry for this variant (Variation ID: 504843). This variant is present in population databases (rs377611164, ExAC 0.02%). This sequence change replaces serine with leucine at codon 164 of the OTOGL protein (p.Ser164Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Vest4
0.86
MVP
0.46
MPC
0.14
ClinPred
D
GERP RS
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at