rs114242958

Positions:

• chr11-17634898-G-A
• chr11-17634898-G-C

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.7535G>A​(p.Arg2512His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00606 in 1,428,630 control chromosomes in the GnomAD database, including 422 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (233 hom., cov: 31)
  • Exomes 𝑓: 0.0032 (189 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.94

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001714617).
• BP6: Variant 11-17634898-G-A is Benign according to our data. Variant chr11-17634898-G-A is described in ClinVar as [Benign]. Clinvar id is 226910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17634898-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.7535G>A	p.Arg2512His	missense_variant	45/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.7571G>A	p.Arg2524His	missense_variant	44/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.7535G>A	p.Arg2512His	missense_variant	45/56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.7571G>A	p.Arg2524His	missense_variant	44/55	5		ENSP00000382323.2
OTOG	ENST00000342528.2	n.4606-712G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0313 AC: 4541 AN: 145236 Hom.: 233 Cov.: 31

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000244

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000274

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.00590 AC: 862 AN: 146140 Hom.: 37 AF XY: 0.00476 AC XY: 376 AN XY: 78932

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.00404

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000311

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000279

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00320 AC: 4112 AN: 1283242 Hom.: 189 Cov.: 34 AF XY: 0.00277 AC XY: 1752 AN XY: 631794

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.00554

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000394

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000140

Gnomad4 OTH exome AF: 0.00723

GnomAD4 genome AF: 0.0313 AC: 4544 AN: 145388 Hom.: 233 Cov.: 31 AF XY: 0.0302 AC XY: 2141 AN XY: 70790

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000274

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0137 Hom.: 43

Bravo AF: 0.0337

ExAC AF: 0.00567 AC: 116

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 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	Arg2524His in exon 44 of OTOG: This variant is not expected to have clinical sig nificance because it has been identified in 13.6% (24/176) of Yoruba (Nigerian) chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi .nlm.nih.gov/projects/SNP; dbSNP rs114242958). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.45
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.69	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Benign	0.061
Sift	Uncertain	0.011	D;.
Sift4G	Uncertain	0.0050	D;D
Vest4		0.12
MVP		0.17
ClinPred		0.024	T
GERP RS		4.7
Varity_R		0.11
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs114242958; hg19: chr11-17656445;