12-80329046-T-C

Position:

• chr12-80329046-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001378609.3(OTOGL):​c.4280-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000896 in 1,588,454 control chromosomes in the GnomAD database, including 2 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00090 (2 hom.)
• Consequence: OTOGL NM_001378609.3 splice_region, intron
• Scores: Splicing: ADA: 0.0004341
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.32

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 12-80329046-T-C is Benign according to our data. Variant chr12-80329046-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 504847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.4280-5T>C		splice_region_variant, intron_variant		ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.4280-5T>C		splice_region_variant, intron_variant		5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1	c.4145-5T>C		splice_region_variant, intron_variant				ENSP00000496036.1

Frequencies

GnomAD3 genomes AF: 0.000887 AC: 135 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000778 AC: 169 AN: 217106 Hom.: 0 AF XY: 0.000808 AC XY: 95 AN XY: 117520

Gnomad AFR exome AF: 0.000281

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00262

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.000898 AC: 1289 AN: 1436210 Hom.: 2 Cov.: 30 AF XY: 0.000840 AC XY: 599 AN XY: 713220

Gnomad4 AFR exome AF: 0.000124

Gnomad4 AMR exome AF: 0.0000258

Gnomad4 ASJ exome AF: 0.0000401

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.00286

Gnomad4 NFE exome AF: 0.000987

Gnomad4 OTH exome AF: 0.000725

GnomAD4 genome AF: 0.000887 AC: 135 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.00101 AC XY: 75 AN XY: 74388

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00119 Hom.: 0

Bravo AF: 0.000521

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 05, 2017

c.4253-5T>C in intron 35 of OTOGL: This variant is not expected to have clinical significance because a T>C change at this position does not diverge from the sp lice consensus sequence and is therefore unlikely to impact splicing. In additio n, it has been identified in 0.26% (66/24918) of Finnish chromosomes by the Geno me Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs20088 9330). -

OTOGL-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 05, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00043
dbscSNV1_RF	Benign	0.012
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: rs200889330; hg19: chr12-80722826;