rs113745835

Positions:

• chr11-17573095-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001292063.2(OTOG):​c.2098G>A​(p.Ala700Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000867 in 1,548,268 control chromosomes in the GnomAD database, including 13 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (8 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.461

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=0.014062047).
• BP6: Variant 11-17573095-G-A is Benign according to our data. Variant chr11-17573095-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00433 (659/152254) while in subpopulation AFR AF= 0.0147 (610/41560). AF 95% confidence interval is 0.0137. There are 5 homozygotes in gnomad4. There are 314 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.2098G>A	p.Ala700Thr	missense_variant	19/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.2134G>A	p.Ala712Thr	missense_variant	18/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.2098G>A	p.Ala700Thr	missense_variant	19/56	5	NM_001292063.2	ENSP00000382329	P2
OTOG	ENST00000399391.7	c.2134G>A	p.Ala712Thr	missense_variant	18/55	5		ENSP00000382323	A2

Frequencies

GnomAD3 genomes AF: 0.00429 AC: 653 AN: 152136 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00113 AC: 164 AN: 145464 Hom.: 2 AF XY: 0.000803 AC XY: 63 AN XY: 78502

Gnomad AFR exome AF: 0.0173

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.00156

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000555

Gnomad OTH exome AF: 0.000939

GnomAD4 exome AF: 0.000489 AC: 683 AN: 1396014 Hom.: 8 Cov.: 32 AF XY: 0.000407 AC XY: 280 AN XY: 688660

Gnomad4 AFR exome AF: 0.0142

Gnomad4 AMR exome AF: 0.00140

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000269

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00433 AC: 659 AN: 152254 Hom.: 5 Cov.: 33 AF XY: 0.00422 AC XY: 314 AN XY: 74444

Gnomad4 AFR AF: 0.0147

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00260 Hom.: 0

Bravo AF: 0.00495

ExAC AF: 0.00110 AC: 30

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	OTOG: BP4, BS1, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 21, 2015

p.Ala712Thr in exon 18 of OTOG: This variant is not expected to have clinical si gnificance because it has been identified in 1.6% (15/918) of African chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs113745835). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.093	T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.85	D;D
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.95	N;.
REVEL	Benign	0.20
Sift	Benign	0.083	T;.
Sift4G	Benign	0.075	T;T
Vest4		0.050
MVP		0.27
ClinPred		0.017	T
GERP RS		-9.8
Varity_R		0.076
gMVP		0.31

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: rs113745835; hg19: chr11-17594642;