rs189159426

chr11-17558218-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001292063.2(OTOG):c.899A>G(p.His300Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00356 in 1,550,464 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (7 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: 4.26

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008020282).
• BP6: Variant 11-17558218-A-G is Benign according to our data. Variant chr11-17558218-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 229109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.899A>G	p.His300Arg	missense_variant	9/56	ENST00000399397.6
OTOG	NM_001277269.2	c.935A>G	p.His312Arg	missense_variant	8/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.899A>G	p.His300Arg	missense_variant	9/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.935A>G	p.His312Arg	missense_variant	8/55	5		A2
OTOG	ENST00000498332.5	n.805A>G		non_coding_transcript_exon_variant	8/16	5
OTOG	ENST00000485669.1	n.405-244A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00243 AC: 370 AN: 152094 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00396

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00235 AC: 350 AN: 149182 Hom.: 2 AF XY: 0.00241 AC XY: 194 AN XY: 80338

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00464

Gnomad ASJ exome AF: 0.000119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000444

Gnomad FIN exome AF: 0.000297

Gnomad NFE exome AF: 0.00367

Gnomad OTH exome AF: 0.00394

GnomAD4 exome AF: 0.00369 AC: 5155 AN: 1398254 Hom.: 7 Cov.: 31 AF XY: 0.00364 AC XY: 2511 AN XY: 689662

Gnomad4 AFR exome AF: 0.000665

Gnomad4 AMR exome AF: 0.00490

Gnomad4 ASJ exome AF: 0.000477

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.000332

Gnomad4 NFE exome AF: 0.00436

Gnomad4 OTH exome AF: 0.00376

GnomAD4 genome AF: 0.00243 AC: 370 AN: 152210 Hom.: 2 Cov.: 32 AF XY: 0.00202 AC XY: 150 AN XY: 74412

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00396

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00296 Hom.: 1

Bravo AF: 0.00271

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00441 AC: 17

ExAC AF: 0.000854 AC: 20

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	OTOG: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2021	- -

Autosomal recessive nonsyndromic hearing loss 18B Uncertain:1

Uncertain significance, no assertion criteria provided

research

Division of Human Genetics, Children's Hospital of Philadelphia

Nov 03, 2015

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 18, 2018

p.His312Arg variant in exon 8 of OTOG: This variant is not expected to have clin ical significance because it has been identified in 0.454% (112/24678) of Latino chromosomes, including 1 homozygous individual, by the Genome Aggregation Datab ase (gnomAD, http://gnomad.broadinstitute.org; rs189159426). In addition, histid ine (His) at position 312 is not conserved through species, with two mammals (pa cific walrus and hedgehog) having an arginine (Arg) at this position. ACMG/AMP C riteria applied: BS1, BP4. -

OTOG-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 26, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0080	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	0.56	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.8	N;.
REVEL	Benign	0.044
Sift	Uncertain	0.012	D;.
Sift4G	Uncertain	0.024	D;D
Vest4		0.26
MVP		0.21
ClinPred		0.016	T
GERP RS		4.5
Varity_R		0.15
gMVP		0.69

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: rs189159426; hg19: chr11-17579765;