rs11024357

chr11-17645892-G-C

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.8690G>C(p.Trp2897Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,550,390 control chromosomes in the GnomAD database, including 39,302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3050 hom., cov: 32)
  • Exomes 𝑓: 0.22 (36252 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 9.16

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 (MetaRNN=0.0016483366).
• BP6: Variant 11-17645892-G-C is Benign according to our data. Variant chr11-17645892-G-C is described in ClinVar as [Benign]. Clinvar id is 226923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17645892-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.8690G>C	p.Trp2897Ser	missense_variant	56/56	ENST00000399397.6
OTOG	NM_001277269.2	c.8726G>C	p.Trp2909Ser	missense_variant	55/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.8690G>C	p.Trp2897Ser	missense_variant	56/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.8726G>C	p.Trp2909Ser	missense_variant	55/55	5		A2

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29999 AN: 152128 Hom.: 3056 Cov.: 32

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.0712

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.232

Gnomad OTH AF: 0.187

GnomAD3 exomes AF: 0.200 AC: 29800 AN: 148742 Hom.: 3352 AF XY: 0.210 AC XY: 16858 AN XY: 80180

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.190

Gnomad EAS exome AF: 0.0682

Gnomad SAS exome AF: 0.277

Gnomad FIN exome AF: 0.239

Gnomad NFE exome AF: 0.232

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.224 AC: 313121 AN: 1398144 Hom.: 36252 Cov.: 35 AF XY: 0.226 AC XY: 155598 AN XY: 689584

Gnomad4 AFR exome AF: 0.150

Gnomad4 AMR exome AF: 0.120

Gnomad4 ASJ exome AF: 0.184

Gnomad4 EAS exome AF: 0.0899

Gnomad4 SAS exome AF: 0.272

Gnomad4 FIN exome AF: 0.238

Gnomad4 NFE exome AF: 0.232

Gnomad4 OTH exome AF: 0.207

GnomAD4 genome AF: 0.197 AC: 30000 AN: 152246 Hom.: 3050 Cov.: 32 AF XY: 0.197 AC XY: 14667 AN XY: 74432

Gnomad4 AFR AF: 0.153

Gnomad4 AMR AF: 0.160

Gnomad4 ASJ AF: 0.171

Gnomad4 EAS AF: 0.0714

Gnomad4 SAS AF: 0.268

Gnomad4 FIN AF: 0.241

Gnomad4 NFE AF: 0.232

Gnomad4 OTH AF: 0.187

Alfa AF: 0.213 Hom.: 1244

Bravo AF: 0.183

TwinsUK AF: 0.225 AC: 834

ALSPAC AF: 0.240 AC: 926

ExAC AF: 0.205 AC: 4346

Asia WGS AF: 0.170 AC: 594 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	Aug 03, 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	Trp2909Ser in exon 55 of OTOG: This variant is not expected to have clinical sig nificance because it has been identified in 32.1% (9/28) of Spanish (Iberian) ch romosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.n lm.nih.gov/projects/SNP; dbSNP rs11024357). -

Autosomal recessive nonsyndromic hearing loss 18B Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 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
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.71	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.41	N;.
MutationTaster	Benign	1.3e-11	P;P
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.3	D;.
REVEL	Uncertain	0.31
Sift	Benign	0.29	T;.
Sift4G	Pathogenic	0.0	D;D
Vest4		0.27
ClinPred		0.014	T
GERP RS		5.3
Varity_R		0.54
gMVP		0.36

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: rs11024357; hg19: chr11-17667439; COSMIC: COSV68038598;