rs12277962

Positions:

• chr11-17634292-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001292063.2(OTOG):​c.7480+11A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,547,726 control chromosomes in the GnomAD database, including 22,022 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1791 hom., cov: 32)
  • Exomes 𝑓: 0.17 (20231 hom.)
• Consequence: OTOG NM_001292063.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.465

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-17634292-A-T is Benign according to our data. Variant chr11-17634292-A-T is described in ClinVar as [Benign]. Clinvar id is 226909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17634292-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.7480+11A>T		intron_variant		ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.7516+11A>T		intron_variant			NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.7480+11A>T		intron_variant		5	NM_001292063.2	ENSP00000382329	P2
OTOG	ENST00000399391.7	c.7516+11A>T		intron_variant		5		ENSP00000382323	A2
OTOG	ENST00000342528.2	n.4605+418A>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22343 AN: 151984 Hom.: 1786 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.00560

Gnomad SAS AF: 0.0996

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.140

GnomAD3 exomes AF: 0.127 AC: 18548 AN: 146340 Hom.: 1399 AF XY: 0.129 AC XY: 10148 AN XY: 78894

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.0750

Gnomad ASJ exome AF: 0.138

Gnomad EAS exome AF: 0.000742

Gnomad SAS exome AF: 0.101

Gnomad FIN exome AF: 0.135

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.122

GnomAD4 exome AF: 0.165 AC: 230452 AN: 1395624 Hom.: 20231 Cov.: 32 AF XY: 0.163 AC XY: 112280 AN XY: 687922

Gnomad4 AFR exome AF: 0.144

Gnomad4 AMR exome AF: 0.0803

Gnomad4 ASJ exome AF: 0.135

Gnomad4 EAS exome AF: 0.00854

Gnomad4 SAS exome AF: 0.106

Gnomad4 FIN exome AF: 0.138

Gnomad4 NFE exome AF: 0.181

Gnomad4 OTH exome AF: 0.150

GnomAD4 genome AF: 0.147 AC: 22363 AN: 152102 Hom.: 1791 Cov.: 32 AF XY: 0.142 AC XY: 10529 AN XY: 74336

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.110

Gnomad4 ASJ AF: 0.124

Gnomad4 EAS AF: 0.00561

Gnomad4 SAS AF: 0.0987

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.178

Gnomad4 OTH AF: 0.138

Alfa AF: 0.155 Hom.: 352

Bravo AF: 0.146

Asia WGS AF: 0.0620 AC: 215 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 2018	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	7516+11A>T in intron 43 of OTOG: This variant is not expected to have clinical s ignificance because it is not located within the conserved splice consensus sequ ence. It has been identified in 25.3% (43/170) of European American chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov /projects/SNP; dbSNP rs12277962). -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.069
DANN	Benign	0.23

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: rs12277962; hg19: chr11-17655839;