rs7130190

chr11-17558628-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.1087A>T(p.Thr363Ser) variant causes a missense change. The variant allele was found at a frequency of 0.148 in 1,549,744 control chromosomes in the GnomAD database, including 17,927 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1393 hom., cov: 33)
  • Exomes 𝑓: 0.15 (16534 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.16

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=0.0018491149).
• BP6: Variant 11-17558628-A-T is Benign according to our data. Variant chr11-17558628-A-T is described in ClinVar as [Benign]. Clinvar id is 226860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17558628-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.1087A>T	p.Thr363Ser	missense_variant	10/56	ENST00000399397.6
OTOG	NM_001277269.2	c.1123A>T	p.Thr375Ser	missense_variant	9/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.1087A>T	p.Thr363Ser	missense_variant	10/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.1123A>T	p.Thr375Ser	missense_variant	9/55	5		A2
OTOG	ENST00000498332.5	n.993A>T		non_coding_transcript_exon_variant	9/16	5
OTOG	ENST00000485669.1			downstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20057 AN: 152012 Hom.: 1394 Cov.: 33

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.0802

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0874

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.137

GnomAD3 exomes AF: 0.122 AC: 17832 AN: 146746 Hom.: 1291 AF XY: 0.123 AC XY: 9753 AN XY: 79192

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.0785

Gnomad ASJ exome AF: 0.176

Gnomad EAS exome AF: 0.000742

Gnomad SAS exome AF: 0.100

Gnomad FIN exome AF: 0.136

Gnomad NFE exome AF: 0.161

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.149 AC: 208720 AN: 1397614 Hom.: 16534 Cov.: 33 AF XY: 0.148 AC XY: 101725 AN XY: 689370

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.0822

Gnomad4 ASJ exome AF: 0.174

Gnomad4 EAS exome AF: 0.00308

Gnomad4 SAS exome AF: 0.0976

Gnomad4 FIN exome AF: 0.137

Gnomad4 NFE exome AF: 0.161

Gnomad4 OTH exome AF: 0.144

GnomAD4 genome AF: 0.132 AC: 20054 AN: 152130 Hom.: 1393 Cov.: 33 AF XY: 0.127 AC XY: 9478 AN XY: 74370

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.174

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.0869

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.158

Gnomad4 OTH AF: 0.135

Alfa AF: 0.151 Hom.: 596

Bravo AF: 0.129

TwinsUK AF: 0.166 AC: 615

ALSPAC AF: 0.156 AC: 601

ExAC AF: 0.0969 AC: 2145

Asia WGS AF: 0.0540 AC: 189 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	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	Thr375Ser in exon 9 of OTOG: This variant is not expected to have clinical signi ficance because it has been identified in 18.5% (33/178) of English and Scottish chromosomes from a broad population by the 1000 Genomes Project (http://www.ncb i.nlm.nih.gov/projects/SNP; dbSNP rs7130190). -

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	0.12
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.033	T;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.73	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.56	N;.
MutationTaster	Benign	0.87	P;P
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.4	N;.
REVEL	Uncertain	0.40
Sift	Benign	0.21	T;.
Sift4G	Benign	0.45	T;T
Vest4		0.061
MutPred		0.59		Gain of disorder (P = 0.1038);.;
ClinPred		0.0059	T
GERP RS		4.9
Varity_R		0.14
gMVP		0.27

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: rs7130190; hg19: chr11-17580175;