rs143393149

chr11-17596943-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001292063.2(OTOG):c.3618C>T(p.Ser1206=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,550,718 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (26 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.19

Genes affected

OTOG (HGNC:8516): (otogelin) The protein encoded by this gene is a component of the acellular membranes of the inner ear. Disruption of the orthologous mouse gene shows that it plays a role in auditory and vestibular functions. It is involved in fibrillar network organization, the anchoring of otoconial membranes and cupulae to the neuroepithelia, and likely in sound stimulation resistance. Mutations in this gene cause autosomal recessive nonsyndromic deafness, type 18B. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 11-17596943-C-T is Benign according to our data. Variant chr11-17596943-C-T is described in ClinVar as [Benign]. Clinvar id is 226889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.19 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00243 (370/152294) while in subpopulation EAS AF= 0.0512 (265/5178). AF 95% confidence interval is 0.0461. There are 6 homozygotes in gnomad4. There are 207 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.3618C>T	p.Ser1206=	synonymous_variant	30/56	ENST00000399397.6
OTOG	NM_001277269.2	c.3654C>T	p.Ser1218=	synonymous_variant	29/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.3618C>T	p.Ser1206=	synonymous_variant	30/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.3654C>T	p.Ser1218=	synonymous_variant	29/55	5		A2
OTOG	ENST00000342528.2	n.983C>T		non_coding_transcript_exon_variant	7/22	2

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 372 AN: 152176 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0514

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00458 AC: 685 AN: 149724 Hom.: 16 AF XY: 0.00449 AC XY: 362 AN XY: 80554

Gnomad AFR exome AF: 0.00132

Gnomad AMR exome AF: 0.000285

Gnomad ASJ exome AF: 0.000119

Gnomad EAS exome AF: 0.0558

Gnomad SAS exome AF: 0.00173

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000541

Gnomad OTH exome AF: 0.00552

GnomAD4 exome AF: 0.00128 AC: 1791 AN: 1398424 Hom.: 26 Cov.: 31 AF XY: 0.00126 AC XY: 868 AN XY: 689736

Gnomad4 AFR exome AF: 0.000601

Gnomad4 AMR exome AF: 0.000252

Gnomad4 ASJ exome AF: 0.0000794

Gnomad4 EAS exome AF: 0.0350

Gnomad4 SAS exome AF: 0.00170

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000639

Gnomad4 OTH exome AF: 0.00527

GnomAD4 genome AF: 0.00243 AC: 370 AN: 152294 Hom.: 6 Cov.: 33 AF XY: 0.00278 AC XY: 207 AN XY: 74460

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0512

Gnomad4 SAS AF: 0.00395

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000556 Hom.: 1

Bravo AF: 0.00250

Asia WGS AF: 0.0340 AC: 117 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ser1218Ser in exon 29 of OTOG: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 3.5% (7/200) of Han Chinese chromosomes from a broad population by the 1000 Genomes Project (http:/ /www.ncbi.nlm.nih.gov/projects/SNP; dbSNP rs143393149). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	2.2
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs143393149; hg19: chr11-17618490; COSMIC: COSV61133551;