rs4756901

chr11-17576640-G-Achr11-17576640-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001292063.2(OTOG):c.2561+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,539,546 control chromosomes in the GnomAD database, including 111,057 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8830 hom., cov: 32)
  • Exomes 𝑓: 0.38 (102227 hom.)
• Consequence: OTOG NM_001292063.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00100

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 -16 ACMG points.

• BP6: Variant 11-17576640-G-A is Benign according to our data. Variant chr11-17576640-G-A is described in ClinVar as [Benign]. Clinvar id is 226870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17576640-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.2561+10G>A		intron_variant		ENST00000399397.6
OTOG	NM_001277269.2	c.2597+10G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.2561+10G>A		intron_variant		5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.2597+10G>A		intron_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.333 AC: 50431 AN: 151644 Hom.: 8831 Cov.: 32

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.334

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.324

GnomAD3 exomes AF: 0.330 AC: 49242 AN: 149210 Hom.: 8568 AF XY: 0.336 AC XY: 27013 AN XY: 80334

Gnomad AFR exome AF: 0.250

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.386

Gnomad EAS exome AF: 0.287

Gnomad SAS exome AF: 0.314

Gnomad FIN exome AF: 0.373

Gnomad NFE exome AF: 0.396

Gnomad OTH exome AF: 0.340

GnomAD4 exome AF: 0.380 AC: 527086 AN: 1387784 Hom.: 102227 Cov.: 32 AF XY: 0.379 AC XY: 259558 AN XY: 685080

Gnomad4 AFR exome AF: 0.250

Gnomad4 AMR exome AF: 0.197

Gnomad4 ASJ exome AF: 0.381

Gnomad4 EAS exome AF: 0.249

Gnomad4 SAS exome AF: 0.316

Gnomad4 FIN exome AF: 0.374

Gnomad4 NFE exome AF: 0.400

Gnomad4 OTH exome AF: 0.365

GnomAD4 genome AF: 0.332 AC: 50436 AN: 151762 Hom.: 8830 Cov.: 32 AF XY: 0.329 AC XY: 24425 AN XY: 74164

Gnomad4 AFR AF: 0.255

Gnomad4 AMR AF: 0.246

Gnomad4 ASJ AF: 0.379

Gnomad4 EAS AF: 0.276

Gnomad4 SAS AF: 0.306

Gnomad4 FIN AF: 0.373

Gnomad4 NFE AF: 0.395

Gnomad4 OTH AF: 0.320

Alfa AF: 0.333 Hom.: 3101

Bravo AF: 0.319

Asia WGS AF: 0.298 AC: 1039 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	2597+10G>A in intron 20 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 43.3% (77/178) of English and Scottish chromosom es from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih. gov/projects/SNP; dbSNP rs4756901). -
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. -

Autosomal recessive nonsyndromic hearing loss 18B Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

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	-0.82
Cadd	Benign	16
Dann	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs4756901; hg19: chr11-17598187; COSMIC: COSV61128336; COSMIC: COSV61128336;