11-17557146-G-A

Position:

• chr11-17557146-G-A

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.688G>A​(p.Ala230Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00505 in 1,550,382 control chromosomes in the GnomAD database, including 321 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (183 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (138 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.433

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=0.0026563108).
• BP6: Variant 11-17557146-G-A is Benign according to our data. Variant chr11-17557146-G-A is described in ClinVar as [Benign]. Clinvar id is 226906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0915 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.688G>A	p.Ala230Thr	missense_variant	8/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.724G>A	p.Ala242Thr	missense_variant	7/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.688G>A	p.Ala230Thr	missense_variant	8/56	5	NM_001292063.2	ENSP00000382329	P2
OTOG	ENST00000399391.7	c.724G>A	p.Ala242Thr	missense_variant	7/55	5		ENSP00000382323	A2
OTOG	ENST00000485669.1	n.227G>A		non_coding_transcript_exon_variant	2/3	4
OTOG	ENST00000498332.5	n.594G>A		non_coding_transcript_exon_variant	7/16	5

Frequencies

GnomAD3 genomes AF: 0.0267 AC: 4063 AN: 152088 Hom.: 184 Cov.: 32

Gnomad AFR AF: 0.0942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00740

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: 0.000162

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.00533 AC: 795 AN: 149192 Hom.: 31 AF XY: 0.00405 AC XY: 325 AN XY: 80312

Gnomad AFR exome AF: 0.0975

Gnomad AMR exome AF: 0.00407

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000133

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000200

Gnomad OTH exome AF: 0.00371

GnomAD4 exome AF: 0.00269 AC: 3758 AN: 1398178 Hom.: 138 Cov.: 32 AF XY: 0.00227 AC XY: 1565 AN XY: 689612

Gnomad4 AFR exome AF: 0.0965

Gnomad4 AMR exome AF: 0.00473

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000177

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000127

Gnomad4 OTH exome AF: 0.00641

GnomAD4 genome AF: 0.0267 AC: 4065 AN: 152204 Hom.: 183 Cov.: 32 AF XY: 0.0260 AC XY: 1936 AN XY: 74400

Gnomad4 AFR AF: 0.0940

Gnomad4 AMR AF: 0.00739

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0128 Hom.: 43

Bravo AF: 0.0303

ExAC AF: 0.00569 AC: 131

Asia WGS AF: 0.00606 AC: 21 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 18, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ala242Thr in exon 7 of OTOG: This variant is not expected to have clinical signi ficance because it has been identified in 13.1% (23/176) of Yoruba (Nigerian) ch romosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.n lm.nih.gov/projects/SNP; dbSNP rs61910753). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.1
DANN	Benign	0.94
DEOGEN2	Benign	0.033	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.40	T;T
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.020	N;.
REVEL	Benign	0.045
Sift	Uncertain	0.0050	D;.
Sift4G	Uncertain	0.026	D;D
Vest4		0.19
MVP		0.085
ClinPred		0.0087	T
GERP RS		-7.3
Varity_R		0.061
gMVP		0.30

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: rs61910753; hg19: chr11-17578693;