rs116947228

chr11-17596999-G-A

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.3674G>A(p.Arg1225His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00447 in 1,549,584 control chromosomes in the GnomAD database, including 200 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (31 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (169 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.718

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=0.0023708344).
• BP6: Variant 11-17596999-G-A is Benign according to our data. Variant chr11-17596999-G-A is described in ClinVar as [Benign]. Clinvar id is 226890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17596999-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0851 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.3674G>A	p.Arg1225His	missense_variant	30/56	ENST00000399397.6
OTOG	NM_001277269.2	c.3710G>A	p.Arg1237His	missense_variant	29/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.3674G>A	p.Arg1225His	missense_variant	30/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.3710G>A	p.Arg1237His	missense_variant	29/55	5		A2
OTOG	ENST00000342528.2	n.1039G>A		non_coding_transcript_exon_variant	7/22	2

Frequencies

GnomAD3 genomes AF: 0.00543 AC: 826 AN: 152128 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0922

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00185

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00837 AC: 1242 AN: 148472 Hom.: 30 AF XY: 0.00808 AC XY: 646 AN XY: 79994

Gnomad AFR exome AF: 0.00133

Gnomad AMR exome AF: 0.000367

Gnomad ASJ exome AF: 0.00144

Gnomad EAS exome AF: 0.0840

Gnomad SAS exome AF: 0.00253

Gnomad FIN exome AF: 0.00819

Gnomad NFE exome AF: 0.00176

Gnomad OTH exome AF: 0.00419

GnomAD4 exome AF: 0.00436 AC: 6099 AN: 1397336 Hom.: 169 Cov.: 31 AF XY: 0.00427 AC XY: 2946 AN XY: 689234

Gnomad4 AFR exome AF: 0.000506

Gnomad4 AMR exome AF: 0.000420

Gnomad4 ASJ exome AF: 0.00135

Gnomad4 EAS exome AF: 0.0908

Gnomad4 SAS exome AF: 0.00249

Gnomad4 FIN exome AF: 0.00855

Gnomad4 NFE exome AF: 0.00167

Gnomad4 OTH exome AF: 0.00647

GnomAD4 genome AF: 0.00541 AC: 824 AN: 152248 Hom.: 31 Cov.: 33 AF XY: 0.00661 AC XY: 492 AN XY: 74424

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0919

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.0120

Gnomad4 NFE AF: 0.00185

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00196 Hom.: 2

Bravo AF: 0.00472

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.00397 AC: 82

Asia WGS AF: 0.0310 AC: 109 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Arg1237His in exon 29 of OTOG: This variant is not expected to have clinical sig nificance because it has been identified in 10.1% (18/178) of Japanese chromosom es from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih. gov/projects/SNP; dbSNP rs116947228). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.047	T;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.76	T;T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	0.98	N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.7	N;.
REVEL	Benign	0.090
Sift	Benign	0.21	T;.
Sift4G	Uncertain	0.0080	D;D
Vest4		0.16
MVP		0.24
ClinPred		0.0037	T
GERP RS		1.8
Varity_R		0.041
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs116947228; hg19: chr11-17618546; COSMIC: COSV61130102;