rs117462138

chr12-80310704-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.3427A>G(p.Ile1143Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,586,528 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (11 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.01

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=0.015127599).
• BP6: Variant 12-80310704-A-G is Benign according to our data. Variant chr12-80310704-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 226942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-80310704-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00238 (362/152286) while in subpopulation NFE AF= 0.0039 (265/68012). AF 95% confidence interval is 0.00351. There are 2 homozygotes in gnomad4. There are 156 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.3427A>G	p.Ile1143Val	missense_variant	30/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.3427A>G	p.Ile1143Val	missense_variant	30/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.3292A>G	p.Ile1098Val	missense_variant	34/63

Frequencies

GnomAD3 genomes AF: 0.00238 AC: 362 AN: 152168 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00390

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00268 AC: 628 AN: 234398 Hom.: 1 AF XY: 0.00269 AC XY: 345 AN XY: 128124

Gnomad AFR exome AF: 0.000396

Gnomad AMR exome AF: 0.00186

Gnomad ASJ exome AF: 0.00772

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.000514

Gnomad NFE exome AF: 0.00411

Gnomad OTH exome AF: 0.00321

GnomAD4 exome AF: 0.00371 AC: 5326 AN: 1434242 Hom.: 11 Cov.: 30 AF XY: 0.00364 AC XY: 2598 AN XY: 714630

Gnomad4 AFR exome AF: 0.000693

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.00737

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000302

Gnomad4 FIN exome AF: 0.000639

Gnomad4 NFE exome AF: 0.00435

Gnomad4 OTH exome AF: 0.00294

GnomAD4 genome AF: 0.00238 AC: 362 AN: 152286 Hom.: 2 Cov.: 33 AF XY: 0.00209 AC XY: 156 AN XY: 74482

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00390

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00384 Hom.: 2

Bravo AF: 0.00230

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.000803 AC: 3

ESP6500EA AF: 0.00402 AC: 33

ExAC AF: 0.00245 AC: 291

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 22, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ile1134Val in exon 29 of OTOGL: This variant is not expected to have clinical si gnificance because it has been identified in 0.4% (33/8204) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs117462138). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

OTOGL-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 13, 2020

This variant is classified as 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	-0.56	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	5.0
Dann	Benign	0.43
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.46	T;.;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
Vest4		0.14
MVP		0.11
MPC		0.021
ClinPred		0.0066	T
GERP RS		0.40
gMVP		0.19

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: rs117462138; hg19: chr12-80704484;