12-80356879-G-A

Variant names:

• chr12-80356879-G-A
• rs11836060
• NM_001378609.3:c.5984G>A

Variant summary

Our verdict is Benign. The variant received -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. 12/18 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:4
• Conservation: PhyloP100: 3.89
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 84B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 226962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.5984G>A	p.Arg1995Gln	missense_variant	Exon 49 of 59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.5984G>A	p.Arg1995Gln	missense_variant	Exon 49 of 59	5	NM_001378609.3	ENSP00000447211.2

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

GnomAD2 exomes AF: 0.174 AC: 41129 AN: 236718 AF XY: 0.177

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 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

African (AFR) AF: 0.172 AC: 5618 AN: 32624

American (AMR) AF: 0.200 AC: 8505 AN: 42466

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 4831 AN: 25684

East Asian (EAS) AF: 0.0355 AC: 1376 AN: 38714

South Asian (SAS) AF: 0.204 AC: 17053 AN: 83392

European-Finnish (FIN) AF: 0.110 AC: 5822 AN: 53028

Middle Eastern (MID) AF: 0.216 AC: 1228 AN: 5698

European-Non Finnish (NFE) AF: 0.199 AC: 218815 AN: 1102274

Other (OTH) AF: 0.186 AC: 11049 AN: 59556

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

African (AFR) AF: 0.180 AC: 7440 AN: 41364

American (AMR) AF: 0.216 AC: 3281 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 648 AN: 3466

East Asian (EAS) AF: 0.0480 AC: 247 AN: 5150

South Asian (SAS) AF: 0.215 AC: 1037 AN: 4818

European-Finnish (FIN) AF: 0.107 AC: 1129 AN: 10520

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.198 AC: 13471 AN: 67920

Other (OTH) AF: 0.188 AC: 397 AN: 2116

Alfa AF: 0.190 Hom.: 9095

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
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
PhyloP100		3.9
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.6	.;.;N
REVEL	Benign	0.066
Sift	Benign	0.34	.;.;T
Sift4G	Benign	0.27	.;.;T
Vest4		0.061
MPC		0.023
ClinPred		0.021	T
GERP RS		4.1
gMVP		0.35
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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