rs875696

chr11-17593702-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001292063.2(OTOG):c.3234C>A(p.Thr1078=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0401 in 1,548,812 control chromosomes in the GnomAD database, including 1,570 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (306 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1264 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.660

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 11-17593702-C-A is Benign according to our data. Variant chr11-17593702-C-A is described in ClinVar as [Benign]. Clinvar id is 226880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.66 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0966 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.3234C>A	p.Thr1078=	synonymous_variant	27/56	ENST00000399397.6
OTOG	NM_001277269.2	c.3270C>A	p.Thr1090=	synonymous_variant	26/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.3234C>A	p.Thr1078=	synonymous_variant	27/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.3270C>A	p.Thr1090=	synonymous_variant	26/55	5		A2
OTOG	ENST00000342528.2	n.599C>A		non_coding_transcript_exon_variant	4/22	2

Frequencies

GnomAD3 genomes AF: 0.0538 AC: 8181 AN: 152094 Hom.: 304 Cov.: 32

Gnomad AFR AF: 0.0989

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0580

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0754

Gnomad FIN AF: 0.0341

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0337

Gnomad OTH AF: 0.0355

GnomAD3 exomes AF: 0.0422 AC: 6258 AN: 148464 Hom.: 205 AF XY: 0.0432 AC XY: 3453 AN XY: 80014

Gnomad AFR exome AF: 0.0983

Gnomad AMR exome AF: 0.0471

Gnomad ASJ exome AF: 0.0255

Gnomad EAS exome AF: 0.000556

Gnomad SAS exome AF: 0.0793

Gnomad FIN exome AF: 0.0326

Gnomad NFE exome AF: 0.0319

Gnomad OTH exome AF: 0.0346

GnomAD4 exome AF: 0.0386 AC: 53946 AN: 1396600 Hom.: 1264 Cov.: 32 AF XY: 0.0395 AC XY: 27220 AN XY: 688840

Gnomad4 AFR exome AF: 0.0989

Gnomad4 AMR exome AF: 0.0459

Gnomad4 ASJ exome AF: 0.0253

Gnomad4 EAS exome AF: 0.000783

Gnomad4 SAS exome AF: 0.0788

Gnomad4 FIN exome AF: 0.0313

Gnomad4 NFE exome AF: 0.0358

Gnomad4 OTH exome AF: 0.0363

GnomAD4 genome AF: 0.0539 AC: 8208 AN: 152212 Hom.: 306 Cov.: 32 AF XY: 0.0553 AC XY: 4117 AN XY: 74422

Gnomad4 AFR AF: 0.0991

Gnomad4 AMR AF: 0.0581

Gnomad4 ASJ AF: 0.0210

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0759

Gnomad4 FIN AF: 0.0341

Gnomad4 NFE AF: 0.0337

Gnomad4 OTH AF: 0.0351

Alfa AF: 0.0357 Hom.: 147

Bravo AF: 0.0542

Asia WGS AF: 0.0510 AC: 178 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Thr1090Thr in exon 26 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 13.4% (26/194) of L uhya (Kenyan) chromosomes from a broad population by the 1000 Genomes Project (h ttp://www.ncbi.nlm.nih.gov/projects/SNP; dbSNP rs875696). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
Cadd	Benign	9.4
Dann	Benign	0.59

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: rs875696; hg19: chr11-17615249;