11-17558628-A-T

Variant names:

• chr11-17558628-A-T
• rs7130190
• NM_001292063.2:c.1087A>T

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: 4.16
• Publications: 10 publications found

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]

OTOG Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 18B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 226860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001292063.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	NM_001292063.2	MANE Select	c.1087A>T	p.Thr363Ser	missense	Exon 10 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.1123A>T	p.Thr375Ser	missense	Exon 9 of 55	NP_001264198.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.1087A>T	p.Thr363Ser	missense	Exon 10 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.1123A>T	p.Thr375Ser	missense	Exon 9 of 55	ENSP00000382323.2
	OTOG	ENST00000498332.5	TSL:5	n.993A>T		non_coding_transcript_exon	Exon 9 of 16

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

GnomAD2 exomes AF: 0.122 AC: 17832 AN: 146746 AF XY: 0.123

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 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

African (AFR) AF: 0.118 AC: 3738 AN: 31596

American (AMR) AF: 0.0822 AC: 2936 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 4375 AN: 25180

East Asian (EAS) AF: 0.00308 AC: 110 AN: 35738

South Asian (SAS) AF: 0.0976 AC: 7737 AN: 79234

European-Finnish (FIN) AF: 0.137 AC: 6514 AN: 47590

Middle Eastern (MID) AF: 0.186 AC: 1060 AN: 5698

European-Non Finnish (NFE) AF: 0.161 AC: 173901 AN: 1078882

Other (OTH) AF: 0.144 AC: 8349 AN: 57992

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

African (AFR) AF: 0.117 AC: 4853 AN: 41496

American (AMR) AF: 0.108 AC: 1644 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 604 AN: 3466

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5168

South Asian (SAS) AF: 0.0869 AC: 419 AN: 4822

European-Finnish (FIN) AF: 0.127 AC: 1340 AN: 10586

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10768 AN: 67988

Other (OTH) AF: 0.135 AC: 286 AN: 2112

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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).

Aug 03, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.56	N
PhyloP100		4.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.40
Sift	Benign	0.21	T
Sift4G	Benign	0.45	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
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7130190; hg19: chr11-17580175; COSMIC: COSV107505963;