11-17645509-T-C

Position:

• chr11-17645509-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001292063.2(OTOG):​c.8462-55T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,521,450 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (37 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (26 hom.)
• Consequence: OTOG NM_001292063.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.245

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=-0.8).
• BP6: Variant 11-17645509-T-C is Benign according to our data. Variant chr11-17645509-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 677073.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.01 (1531/152344) while in subpopulation AFR AF= 0.0349 (1452/41588). AF 95% confidence interval is 0.0334. There are 37 homozygotes in gnomad4. There are 752 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.8462-55T>C		intron_variant		ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.8498-55T>C		intron_variant			NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.8462-55T>C		intron_variant		5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.8498-55T>C		intron_variant		5		ENSP00000382323.2

Frequencies

GnomAD3 genomes AF: 0.00983 AC: 1496 AN: 152226 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.0342

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00573

GnomAD4 exome AF: 0.00105 AC: 1438 AN: 1369106 Hom.: 26 AF XY: 0.000913 AC XY: 616 AN XY: 674664

Gnomad4 AFR exome AF: 0.0363

Gnomad4 AMR exome AF: 0.00203

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000132

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000426

Gnomad4 OTH exome AF: 0.00327

GnomAD4 genome AF: 0.0100 AC: 1531 AN: 152344 Hom.: 37 Cov.: 33 AF XY: 0.0101 AC XY: 752 AN XY: 74502

Gnomad4 AFR AF: 0.0349

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00935 Hom.: 1

Bravo AF: 0.0115

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 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	-0.80
CADD	Benign	2.4
DANN	Benign	0.63

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: rs76783895; hg19: chr11-17667056;