rs73418068

chr11-17570232-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001292063.2(OTOG):c.1797G>A(p.Arg599=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,550,820 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (9 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.77

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 11-17570232-G-A is Benign according to our data. Variant chr11-17570232-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.77 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00644 (981/152314) while in subpopulation AFR AF= 0.0221 (919/41556). AF 95% confidence interval is 0.0209. There are 6 homozygotes in gnomad4. There are 449 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.1797G>A	p.Arg599=	synonymous_variant	17/56	ENST00000399397.6
OTOG	NM_001277269.2	c.1833G>A	p.Arg611=	synonymous_variant	16/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.1797G>A	p.Arg599=	synonymous_variant	17/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.1833G>A	p.Arg611=	synonymous_variant	16/55	5		A2
OTOG	ENST00000498332.5	n.1703G>A		non_coding_transcript_exon_variant	16/16	5

Frequencies

GnomAD3 genomes AF: 0.00643 AC: 979 AN: 152196 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00145 AC: 217 AN: 150144 Hom.: 2 AF XY: 0.00114 AC XY: 92 AN XY: 80588

Gnomad AFR exome AF: 0.0241

Gnomad AMR exome AF: 0.00118

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: 0.000324

Gnomad OTH exome AF: 0.000458

GnomAD4 exome AF: 0.000849 AC: 1188 AN: 1398506 Hom.: 9 Cov.: 30 AF XY: 0.000723 AC XY: 499 AN XY: 689782

Gnomad4 AFR exome AF: 0.0239

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000631

Gnomad4 FIN exome AF: 0.0000207

Gnomad4 NFE exome AF: 0.000249

Gnomad4 OTH exome AF: 0.00188

GnomAD4 genome AF: 0.00644 AC: 981 AN: 152314 Hom.: 6 Cov.: 32 AF XY: 0.00603 AC XY: 449 AN XY: 74482

Gnomad4 AFR AF: 0.0221

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00343 Hom.: 1

Bravo AF: 0.00719

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 03, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Arg611Arg in exon 16 of OTOG: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 5.2% (10/194) of Luh ya (Kenyan) chromosomes from a broad population by the 1000 Genomes Project (htt p://www.ncbi.nlm.nih.gov/projects/SNP; dbSNP rs73418068). -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2022	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
Cadd	Benign	9.6
Dann	Benign	0.76

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: rs73418068; hg19: chr11-17591779;