rs1477766714

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001378609.3(OTOGL):​c.5027C>G​(p.Ser1676Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)

Consequence

OTOGL
NM_001378609.3 stop_gained

Scores

4
1
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.62
Variant links:
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 Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-80339241-C-G is Pathogenic according to our data. Variant chr12-80339241-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495109.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
OTOGLNM_001378609.3 linkuse as main transcriptc.5027C>G p.Ser1676Ter stop_gained 43/59 ENST00000547103.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
OTOGLENST00000547103.7 linkuse as main transcriptc.5027C>G p.Ser1676Ter stop_gained 43/595 NM_001378609.3 P1
OTOGLENST00000646859.1 linkuse as main transcriptc.4892C>G p.Ser1631Ter stop_gained 47/63
OTOGLENST00000298820.7 linkuse as main transcriptc.329C>G p.Ser110Ter stop_gained 4/185

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 84B Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingTehran Medical Genetics LaboratoryOct 05, 2016This variant was found in compound heterozygous form with c.4253G>T/p.C1418F, which is a previously unreported variant but was not submitted to ClinVar. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.36
CADD
Pathogenic
38
DANN
Uncertain
1.0
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Benign
0.75
D
MutationTaster
Benign
1.0
A;A
Vest4
0.43
ClinPred
0.99
D
GERP RS
4.6

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1477766714; hg19: chr12-80733021; COSMIC: COSV100087340; COSMIC: COSV100087340; API