chr11-17594039-C-G

Position:

• chr11-17594039-C-G

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.3289-8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,550,578 control chromosomes in the GnomAD database, including 204 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (12 hom., cov: 32)
  • Exomes 𝑓: 0.014 (192 hom.)
• Consequence: OTOG NM_001292063.2 splice_region, intron
• Scores: Splicing: ADA: 0.002160
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.199

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]

OTOG (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-17594039-C-G is Benign according to our data. Variant chr11-17594039-C-G is described in ClinVar as [Benign]. Clinvar id is 226882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0105 (1602/152324) while in subpopulation NFE AF= 0.0185 (1261/68028). AF 95% confidence interval is 0.0177. There are 12 homozygotes in gnomad4. There are 704 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.3289-8C>G		splice_region_variant, intron_variant		ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.3325-8C>G		splice_region_variant, intron_variant			NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.3289-8C>G		splice_region_variant, intron_variant		5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.3325-8C>G		splice_region_variant, intron_variant		5		ENSP00000382323.2
OTOG	ENST00000342528.2	n.654-8C>G		splice_region_variant, intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1602 AN: 152206 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00861 AC: 1285 AN: 149176 Hom.: 14 AF XY: 0.00851 AC XY: 684 AN XY: 80348

Gnomad AFR exome AF: 0.00266

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.00155

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00257

Gnomad FIN exome AF: 0.0126

Gnomad NFE exome AF: 0.0163

Gnomad OTH exome AF: 0.00928

GnomAD4 exome AF: 0.0138 AC: 19249 AN: 1398254 Hom.: 192 Cov.: 32 AF XY: 0.0134 AC XY: 9265 AN XY: 689642

Gnomad4 AFR exome AF: 0.00253

Gnomad4 AMR exome AF: 0.00185

Gnomad4 ASJ exome AF: 0.00127

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00260

Gnomad4 FIN exome AF: 0.0132

Gnomad4 NFE exome AF: 0.0163

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.0105 AC: 1602 AN: 152324 Hom.: 12 Cov.: 32 AF XY: 0.00945 AC XY: 704 AN XY: 74502

Gnomad4 AFR AF: 0.00238

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0115

Gnomad4 NFE AF: 0.0185

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00713 Hom.: 1

Bravo AF: 0.00913

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 27, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

3325-8C>G in intron 26 of OTOG: This variant is not expected to have clinical si gnificance because it has been identified in 3.2% (6/186) of Finnish chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.go v/projects/SNP; dbSNP rs12792504). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.4
DANN	Benign	0.36

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0022
dbscSNV1_RF	Benign	0.050
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: rs12792504; hg19: chr11-17615586;