rs545740473

chr11-17609927-G-Achr11-17609927-G-Cchr11-17609927-G-T

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.4627G>A(p.Ala1543Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000593 in 1,528,824 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1543A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0032 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.106

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=0.003975302).
• BP6: Variant 11-17609927-G-A is Benign according to our data. Variant chr11-17609927-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.4627G>A	p.Ala1543Thr	missense_variant	36/56	ENST00000399397.6
OTOG	NM_001277269.2	c.4663G>A	p.Ala1555Thr	missense_variant	35/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.4627G>A	p.Ala1543Thr	missense_variant	36/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.4663G>A	p.Ala1555Thr	missense_variant	35/55	5		A2
OTOG	ENST00000342528.2	n.1965G>A		non_coding_transcript_exon_variant	12/22	2

Frequencies

GnomAD3 genomes AF: 0.00316 AC: 479 AN: 151772 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000666 AC: 88 AN: 132102 Hom.: 0 AF XY: 0.000659 AC XY: 46 AN XY: 69828

Gnomad AFR exome AF: 0.0122

Gnomad AMR exome AF: 0.000212

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000211

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000306 AC: 422 AN: 1376934 Hom.: 1 Cov.: 31 AF XY: 0.000262 AC XY: 177 AN XY: 676020

Gnomad4 AFR exome AF: 0.0115

Gnomad4 AMR exome AF: 0.000346

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000266

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000159

Gnomad4 OTH exome AF: 0.000525

GnomAD4 genome AF: 0.00319 AC: 484 AN: 151890 Hom.: 4 Cov.: 32 AF XY: 0.00306 AC XY: 227 AN XY: 74246

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00147 Hom.: 2

Bravo AF: 0.00359

ExAC AF: 0.000292 AC: 8

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	p.Ala1555Thr in exon 35 of OTOG: This variant is not expected to have clinical s ignificance due to a lack of conservation in mammals. Of note, three mammals (sq uirrel, manatee, Cape golden mole) have a threonine (Thr) at this position. It h as been identified in 0.6% (5/774) of African chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs545740473). -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

OTOG-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 02, 2020

This variant is classified as 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	0.073
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	2.5
Dann	Benign	0.51
DEOGEN2	Benign	0.024	T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0040	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.12	N;.
REVEL	Benign	0.031
Sift	Benign	0.43	T;.
Sift4G	Benign	0.38	T;T
Vest4		0.034
MVP		0.040
ClinPred		0.0056	T
GERP RS		3.1
Varity_R		0.040
gMVP		0.33

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: rs545740473; hg19: chr11-17631474;