rs7130051

chr11-17558503-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001292063.2(OTOG):c.997-35A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,548,478 control chromosomes in the GnomAD database, including 20,754 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.17 (2556 hom., cov: 33)
  • Exomes 𝑓: 0.16 (18198 hom.)
• Consequence: OTOG NM_001292063.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.273

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-17558503-A-C is Benign according to our data. Variant chr11-17558503-A-C is described in ClinVar as [Benign]. Clinvar id is 682654.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-17558503-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.997-35A>C		intron_variant		ENST00000399397.6
OTOG	NM_001277269.2	c.1033-35A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.997-35A>C		intron_variant		5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.1033-35A>C		intron_variant		5		A2
OTOG	ENST00000485669.1	n.446A>C		non_coding_transcript_exon_variant	3/3	4
OTOG	ENST00000498332.5	n.903-35A>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26397 AN: 152078 Hom.: 2557 Cov.: 33

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.0802

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0887

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.175

GnomAD3 exomes AF: 0.134 AC: 19587 AN: 146074 Hom.: 1578 AF XY: 0.134 AC XY: 10530 AN XY: 78730

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.0961

Gnomad ASJ exome AF: 0.192

Gnomad EAS exome AF: 0.000742

Gnomad SAS exome AF: 0.102

Gnomad FIN exome AF: 0.138

Gnomad NFE exome AF: 0.165

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.157 AC: 218604 AN: 1396282 Hom.: 18198 Cov.: 32 AF XY: 0.154 AC XY: 106321 AN XY: 688738

Gnomad4 AFR exome AF: 0.250

Gnomad4 AMR exome AF: 0.101

Gnomad4 ASJ exome AF: 0.191

Gnomad4 EAS exome AF: 0.00308

Gnomad4 SAS exome AF: 0.0988

Gnomad4 FIN exome AF: 0.138

Gnomad4 NFE exome AF: 0.165

Gnomad4 OTH exome AF: 0.161

GnomAD4 genome AF: 0.174 AC: 26407 AN: 152196 Hom.: 2556 Cov.: 33 AF XY: 0.167 AC XY: 12456 AN XY: 74392

Gnomad4 AFR AF: 0.247

Gnomad4 AMR AF: 0.138

Gnomad4 ASJ AF: 0.191

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.0879

Gnomad4 FIN AF: 0.129

Gnomad4 NFE AF: 0.163

Gnomad4 OTH AF: 0.173

Alfa AF: 0.164 Hom.: 1128

Bravo AF: 0.178

Asia WGS AF: 0.0640 AC: 225 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	6.4
Dann	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs7130051; hg19: chr11-17580050;