rs113275496

Positions:

• chr11-17596164-C-A
• chr11-17596164-C-T

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.3525+10C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000807 in 1,539,728 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (4 hom.)
• Consequence: OTOG NM_001292063.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0480

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 (BayesDel_noAF=-0.56).
• BP6: Variant 11-17596164-C-A is Benign according to our data. Variant chr11-17596164-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 226888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17596164-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00418 (637/152230) while in subpopulation AFR AF= 0.0145 (602/41532). AF 95% confidence interval is 0.0135. There are 5 homozygotes in gnomad4. There are 284 alleles in male gnomad4 subpopulation. Median coverage is 32. 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.3525+10C>A		intron_variant		ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.3561+10C>A		intron_variant			NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.3525+10C>A		intron_variant		5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.3561+10C>A		intron_variant		5		ENSP00000382323.2
OTOG	ENST00000342528.2	n.890+10C>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00418 AC: 636 AN: 152112 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0145

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: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.000979 AC: 146 AN: 149166 Hom.: 1 AF XY: 0.000760 AC XY: 61 AN XY: 80302

Gnomad AFR exome AF: 0.0165

Gnomad AMR exome AF: 0.00118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000444

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000545

Gnomad OTH exome AF: 0.000232

GnomAD4 exome AF: 0.000437 AC: 606 AN: 1387498 Hom.: 4 Cov.: 28 AF XY: 0.000349 AC XY: 239 AN XY: 685120

Gnomad4 AFR exome AF: 0.0137

Gnomad4 AMR exome AF: 0.00151

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000633

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000449

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.00418 AC: 637 AN: 152230 Hom.: 5 Cov.: 32 AF XY: 0.00382 AC XY: 284 AN XY: 74440

Gnomad4 AFR AF: 0.0145

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00307 Hom.: 1

Bravo AF: 0.00470

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	3561+10C>A in intron 28 of OTOG: This variant is not expected to have clinical s ignificance because it is not located within the conserved splice consensus sequ ence. It has been identified in 2.6% (5/194) of Luhya (Kenyan) chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov/proj ects/SNP; dbSNP rs113275496). -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2018	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	12
DANN	Benign	0.83

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: rs113275496; hg19: chr11-17617711;