rs12316424

Positions:

• chr12-80313505-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378609.3(OTOGL):​c.3480T>C​(p.Cys1160=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,612,322 control chromosomes in the GnomAD database, including 2,357 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (1231 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (1126 hom.)
• Consequence: OTOGL NM_001378609.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.441

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 12-80313505-T-C is Benign according to our data. Variant chr12-80313505-T-C is described in ClinVar as [Benign]. Clinvar id is 226943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.441 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.3480T>C	p.Cys1160=	synonymous_variant	31/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.3480T>C	p.Cys1160=	synonymous_variant	31/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.3345T>C	p.Cys1115=	synonymous_variant	35/63

Frequencies

GnomAD3 genomes AF: 0.0691 AC: 10514 AN: 152094 Hom.: 1230 Cov.: 32

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0272

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.0473

GnomAD3 exomes AF: 0.0179 AC: 4405 AN: 246514 Hom.: 463 AF XY: 0.0133 AC XY: 1780 AN XY: 133936

Gnomad AFR exome AF: 0.247

Gnomad AMR exome AF: 0.0123

Gnomad ASJ exome AF: 0.000697

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000725

Gnomad OTH exome AF: 0.00962

GnomAD4 exome AF: 0.00711 AC: 10378 AN: 1460110 Hom.: 1126 Cov.: 31 AF XY: 0.00608 AC XY: 4419 AN XY: 726436

Gnomad4 AFR exome AF: 0.248

Gnomad4 AMR exome AF: 0.0132

Gnomad4 ASJ exome AF: 0.000766

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000405

Gnomad4 OTH exome AF: 0.0161

GnomAD4 genome AF: 0.0693 AC: 10545 AN: 152212 Hom.: 1231 Cov.: 32 AF XY: 0.0664 AC XY: 4940 AN XY: 74442

Gnomad4 AFR AF: 0.240

Gnomad4 AMR AF: 0.0271

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.0482

Alfa AF: 0.0270 Hom.: 167

Bravo AF: 0.0791

Asia WGS AF: 0.0200 AC: 70 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.00130

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	Cys1151Cys in exon 30 of OTOGL: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 22.3% (963/4318) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs12316424). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 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 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 15, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	8.6
DANN	Benign	0.73

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: rs12316424; hg19: chr12-80707285;