rs186616540

chr12-80238962-G-A

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.929G>A(p.Gly310Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00492 in 1,597,246 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (34 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.28

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=0.0076597035).
• BP6: Variant 12-80238962-G-A is Benign according to our data. Variant chr12-80238962-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-80238962-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00309 (471/152228) while in subpopulation NFE AF= 0.00513 (349/67996). AF 95% confidence interval is 0.00469. There are 3 homozygotes in gnomad4. There are 229 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.929G>A	p.Gly310Glu	missense_variant	10/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.929G>A	p.Gly310Glu	missense_variant	10/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.929G>A	p.Gly310Glu	missense_variant	15/63
OTOGL	ENST00000643417.1	n.1589G>A		non_coding_transcript_exon_variant	13/23

Frequencies

GnomAD3 genomes AF: 0.00310 AC: 472 AN: 152110 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00515

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00268 AC: 621 AN: 231836 Hom.: 3 AF XY: 0.00261 AC XY: 330 AN XY: 126642

Gnomad AFR exome AF: 0.000998

Gnomad AMR exome AF: 0.000709

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000201

Gnomad FIN exome AF: 0.00363

Gnomad NFE exome AF: 0.00478

Gnomad OTH exome AF: 0.00290

GnomAD4 exome AF: 0.00512 AC: 7393 AN: 1445018 Hom.: 34 Cov.: 32 AF XY: 0.00490 AC XY: 3522 AN XY: 719058

Gnomad4 AFR exome AF: 0.000808

Gnomad4 AMR exome AF: 0.000971

Gnomad4 ASJ exome AF: 0.0000767

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000268

Gnomad4 FIN exome AF: 0.00399

Gnomad4 NFE exome AF: 0.00624

Gnomad4 OTH exome AF: 0.00332

GnomAD4 genome AF: 0.00309 AC: 471 AN: 152228 Hom.: 3 Cov.: 32 AF XY: 0.00308 AC XY: 229 AN XY: 74448

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00377

Gnomad4 NFE AF: 0.00513

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00429 Hom.: 1

Bravo AF: 0.00273

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00132 AC: 5

ESP6500EA AF: 0.00303 AC: 25

ExAC AF: 0.00252 AC: 300

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	OTOGL: BP4, BS2 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Gly301Glu in exon 9 of OTOGL: This variant is not expected to have clinical sign ificance because it has been identified in 0.3% (25/8238) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs186616540). -

OTOGL-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 13, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	22
Dann	Benign	0.65
Eigen	Benign	0.087
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.56	T;.;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.0077	T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	0.97	N;N
PrimateAI	Uncertain	0.50	T
Vest4		0.26
MVP		0.13
MPC		0.027
ClinPred		0.013	T
GERP RS		4.3
gMVP		0.38

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: rs186616540; hg19: chr12-80632742; COSMIC: COSV105363084;