rs775349315
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001378609.3(OTOGL):c.242G>A(p.Cys81Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000258 in 1,548,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000014 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
OTOGL
NM_001378609.3 missense
NM_001378609.3 missense
Scores
3
6
3
Clinical Significance
Conservation
PhyloP100: 7.97
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 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.927
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOGL | NM_001378609.3 | c.242G>A | p.Cys81Tyr | missense_variant | 6/59 | ENST00000547103.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOGL | ENST00000547103.7 | c.242G>A | p.Cys81Tyr | missense_variant | 6/59 | 5 | NM_001378609.3 | P1 | |
OTOGL | ENST00000646859.1 | c.242G>A | p.Cys81Tyr | missense_variant | 11/63 | ||||
OTOGL | ENST00000643417.1 | n.902G>A | non_coding_transcript_exon_variant | 9/23 |
Frequencies
GnomAD3 genomes ? AF: 0.0000136 AC: 2AN: 146618Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000461 AC: 1AN: 216742Hom.: 0 AF XY: 0.00000846 AC XY: 1AN XY: 118272
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GnomAD4 exome AF: 0.00000143 AC: 2AN: 1401674Hom.: 0 Cov.: 30 AF XY: 0.00000143 AC XY: 1AN XY: 698988
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GnomAD4 genome ? AF: 0.0000136 AC: 2AN: 146618Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 71234
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 16, 2021 | The p.Cys72Tyr variant in OTOGL has not been previously reported in individuals with hearing loss but has been identified in 0.00098% (1/102300) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;.;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Vest4
0.82
MutPred
0.86
.;.;Gain of disorder (P = 0.0643);
MVP
0.19
MPC
0.22
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