rs149249642

Positions:

• chr12-80366589-A-G

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.6283A>G​(p.Ile2095Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000748 in 1,404,176 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 26)
  • Exomes 𝑓: 0.00063 (4 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.545

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]

OTOGL (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008036017).
• BP6: Variant 12-80366589-A-G is Benign according to our data. Variant chr12-80366589-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 226967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-80366589-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00175 (259/148198) while in subpopulation AFR AF= 0.00391 (160/40882). AF 95% confidence interval is 0.00342. There are 1 homozygotes in gnomad4. There are 117 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.6283A>G	p.Ile2095Val	missense_variant	53/59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.6283A>G	p.Ile2095Val	missense_variant	53/59	5	NM_001378609.3	ENSP00000447211.2

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 259 AN: 148174 Hom.: 1 Cov.: 26

Gnomad AFR AF: 0.00390

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00272

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00662

Gnomad NFE AF: 0.000713

Gnomad OTH AF: 0.00440

GnomAD3 exomes AF: 0.000905 AC: 157 AN: 173430 Hom.: 0 AF XY: 0.000842 AC XY: 81 AN XY: 96144

Gnomad AFR exome AF: 0.00389

Gnomad AMR exome AF: 0.00161

Gnomad ASJ exome AF: 0.000734

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000471

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000727

Gnomad OTH exome AF: 0.00253

GnomAD4 exome AF: 0.000631 AC: 792 AN: 1255978 Hom.: 4 Cov.: 21 AF XY: 0.000623 AC XY: 387 AN XY: 621326

Gnomad4 AFR exome AF: 0.00448

Gnomad4 AMR exome AF: 0.00218

Gnomad4 ASJ exome AF: 0.000424

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000372

Gnomad4 FIN exome AF: 0.0000673

Gnomad4 NFE exome AF: 0.000447

Gnomad4 OTH exome AF: 0.00200

GnomAD4 genome AF: 0.00175 AC: 259 AN: 148198 Hom.: 1 Cov.: 26 AF XY: 0.00162 AC XY: 117 AN XY: 72100

Gnomad4 AFR AF: 0.00391

Gnomad4 AMR AF: 0.00265

Gnomad4 ASJ AF: 0.000290

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000713

Gnomad4 OTH AF: 0.00437

Alfa AF: 0.000850 Hom.: 0

Bravo AF: 0.00212

ESP6500AA AF: 0.00273 AC: 12

ESP6500EA AF: 0.000350 AC: 3

ExAC AF: 0.000923 AC: 110

Asia WGS AF: 0.00146 AC: 5 AN: 3446

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Ile2086Val in exon 52 of OTOGL: This variant is not expected to have clinical si gnificance because it has been identified in 4.6% (9/194) of Luhya (Kenyan) chro mosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm .nih.gov/projects/SNP; dbSNP rs149249642). -

OTOGL-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2023

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_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	10
DANN	Benign	0.96
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.40	T;.;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.0080	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.67	.;.;N
REVEL	Benign	0.026
Sift	Benign	0.31	.;.;T
Sift4G	Benign	0.33	.;.;T
Vest4		0.13
MVP		0.030
MPC		0.021
ClinPred		0.0013	T
GERP RS		-1.6
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs149249642; hg19: chr12-80760369;