rs367996419

Positions:

• chr12-80254580-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_001378609.3(OTOGL):​c.1441+10T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000849 in 1,599,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (0 hom.)
• Consequence: OTOGL NM_001378609.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.154

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 12-80254580-T-A is Benign according to our data. Variant chr12-80254580-T-A is described in ClinVar as [Benign]. Clinvar id is 227811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-80254580-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000874 (1264/1446948) while in subpopulation AMR AF= 0.0038 (169/44474). AF 95% confidence interval is 0.00333. There are 0 homozygotes in gnomad4_exome. There are 613 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.1441+10T>A		intron_variant		ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.1441+10T>A		intron_variant		5	NM_001378609.3	ENSP00000447211	P1
OTOGL	ENST00000646859.1	c.1441+10T>A		intron_variant				ENSP00000496036
OTOGL	ENST00000643417.1	n.2101+10T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000619 AC: 94 AN: 151934 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000574

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000981 AC: 240 AN: 244652 Hom.: 0 AF XY: 0.000917 AC XY: 122 AN XY: 132980

Gnomad AFR exome AF: 0.000326

Gnomad AMR exome AF: 0.00383

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00190

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000604

Gnomad OTH exome AF: 0.000669

GnomAD4 exome AF: 0.000874 AC: 1264 AN: 1446948 Hom.: 0 Cov.: 29 AF XY: 0.000851 AC XY: 613 AN XY: 720140

Gnomad4 AFR exome AF: 0.000271

Gnomad4 AMR exome AF: 0.00380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00228

Gnomad4 SAS exome AF: 0.000106

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000835

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.000618 AC: 94 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.000673 AC XY: 50 AN XY: 74338

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00184

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000574

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000430 Hom.: 0

Bravo AF: 0.000880

Asia WGS AF: 0.000868 AC: 3 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 13, 2017

c.1414+10T>A in intron 14 of OTOGL: This variant is not expected to have clinica l significance because it is not located within the splice consensus sequence. I t has been identified in 0.4% (131/34138) of Latino chromosomes by the Genome Ag gregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs367996419) . -

OTOGL-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.30
DANN	Benign	0.71

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: rs367996419; hg19: chr12-80648360;