rs79120261

Positions:

• chr12-80352288-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378609.3(OTOGL):​c.5266-7T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 1,602,594 control chromosomes in the GnomAD database, including 809 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 0.021 (56 hom., cov: 33)
  • Exomes 𝑓: 0.029 (753 hom.)
• Consequence: OTOGL NM_001378609.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004058
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.90

Genes affected

OTOGL (HGNC:26901): (otogelin like) The protein encoded by this gene belongs to the otogelin family. This gene is expressed in the inner ear of vertebrates with the highest level of expression seen at the embryonic stage and lowest in adult. Knockdown studies in zebrafish suggest that this gene is essential for normal inner ear function. Mutations in this gene are associated with autosomal recessive deafness. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 12-80352288-T-C is Benign according to our data. Variant chr12-80352288-T-C is described in ClinVar as [Benign]. Clinvar id is 226954.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 = 0.0205 (3123/152284) while in subpopulation NFE AF= 0.0319 (2170/68008). AF 95% confidence interval is 0.0308. There are 56 homozygotes in gnomad4. There are 1429 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 56 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.5266-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.5266-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001378609.3	P1
OTOGL	ENST00000298820.7	c.567-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5
OTOGL	ENST00000646859.1	c.5131-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3122 AN: 152166 Hom.: 55 Cov.: 33

Gnomad AFR AF: 0.00649

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0286

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.00754

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0319

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.0196 AC: 4609 AN: 235408 Hom.: 63 AF XY: 0.0202 AC XY: 2578 AN XY: 127808

Gnomad AFR exome AF: 0.00601

Gnomad AMR exome AF: 0.0155

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.000115

Gnomad SAS exome AF: 0.00480

Gnomad FIN exome AF: 0.00737

Gnomad NFE exome AF: 0.0317

Gnomad OTH exome AF: 0.0256

GnomAD4 exome AF: 0.0292 AC: 42280 AN: 1450310 Hom.: 753 Cov.: 30 AF XY: 0.0287 AC XY: 20672 AN XY: 721204

Gnomad4 AFR exome AF: 0.00638

Gnomad4 AMR exome AF: 0.0165

Gnomad4 ASJ exome AF: 0.0195

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.00511

Gnomad4 FIN exome AF: 0.00711

Gnomad4 NFE exome AF: 0.0346

Gnomad4 OTH exome AF: 0.0257

GnomAD4 genome AF: 0.0205 AC: 3123 AN: 152284 Hom.: 56 Cov.: 33 AF XY: 0.0192 AC XY: 1429 AN XY: 74462

Gnomad4 AFR AF: 0.00654

Gnomad4 AMR AF: 0.0285

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00684

Gnomad4 FIN AF: 0.00754

Gnomad4 NFE AF: 0.0319

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0281 Hom.: 32

Bravo AF: 0.0214

Asia WGS AF: 0.00433 AC: 15 AN: 3476

ClinVar

Significance: 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	5239-7T>C in intron 43 of OTOGL: This variant is not expected to have clinical s ignificance because it has been identified in 3.3% (268/8158) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs79120261). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2017	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:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	13
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00041
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.070		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: rs79120261; hg19: chr12-80746068;