rs11836060

chr12-80356879-G-Achr12-80356879-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378609.3(OTOGL):c.5984G>A(p.Arg1995Gln) variant causes a missense change. The variant allele was found at a frequency of 0.189 in 1,595,220 control chromosomes in the GnomAD database, including 30,055 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1995G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.18 (2731 hom., cov: 31)
  • Exomes 𝑓: 0.19 (27324 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.89

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 (MetaRNN=0.0010064244).
• BP6: Variant 12-80356879-G-A is Benign according to our data. Variant chr12-80356879-G-A is described in ClinVar as [Benign]. Clinvar id is 226962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-80356879-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.5984G>A	p.Arg1995Gln	missense_variant	49/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.5984G>A	p.Arg1995Gln	missense_variant	49/59	5	NM_001378609.3	P1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27972 AN: 151668 Hom.: 2730 Cov.: 31

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.0478

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.190

GnomAD3 exomes AF: 0.174 AC: 41129 AN: 236718 Hom.: 3972 AF XY: 0.177 AC XY: 22731 AN XY: 128616

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.0399

Gnomad SAS exome AF: 0.207

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.193

Gnomad OTH exome AF: 0.182

GnomAD4 exome AF: 0.190 AC: 274297 AN: 1443436 Hom.: 27324 Cov.: 31 AF XY: 0.191 AC XY: 136974 AN XY: 717914

Gnomad4 AFR exome AF: 0.172

Gnomad4 AMR exome AF: 0.200

Gnomad4 ASJ exome AF: 0.188

Gnomad4 EAS exome AF: 0.0355

Gnomad4 SAS exome AF: 0.204

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.199

Gnomad4 OTH exome AF: 0.186

GnomAD4 genome AF: 0.184 AC: 27974 AN: 151784 Hom.: 2731 Cov.: 31 AF XY: 0.181 AC XY: 13441 AN XY: 74164

Gnomad4 AFR AF: 0.180

Gnomad4 AMR AF: 0.216

Gnomad4 ASJ AF: 0.187

Gnomad4 EAS AF: 0.0480

Gnomad4 SAS AF: 0.215

Gnomad4 FIN AF: 0.107

Gnomad4 NFE AF: 0.198

Gnomad4 OTH AF: 0.188

Alfa AF: 0.190 Hom.: 5785

Bravo AF: 0.192

TwinsUK AF: 0.193 AC: 714

ALSPAC AF: 0.199 AC: 767

ESP6500AA AF: 0.187 AC: 823

ESP6500EA AF: 0.197 AC: 1690

ExAC AF: 0.182 AC: 22088

Asia WGS AF: 0.140 AC: 484 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Arg1986Gln in exon 48 of OTOGL: This variant is not expected to have clinical si gnificance because it has been identified in 19.7% (1690/8600) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs11836060). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.36	T;.;T
MetaRNN	Benign	0.0010	T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.26	T
Vest4		0.061
MPC		0.023
ClinPred		0.021	T
GERP RS		4.1
gMVP		0.35

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: rs11836060; hg19: chr12-80750659; COSMIC: COSV54020791; COSMIC: COSV54020791;