chr12-80353462-A-G

Variant names:

• chr12-80353462-A-G
• rs7297767
• NM_001378609.3:c.5545A>G

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.5545A>G​(p.Ile1849Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.852 in 1,599,948 control chromosomes in the GnomAD database, including 580,701 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (53660 hom., cov: 32)
  • Exomes 𝑓: 0.85 (527041 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.979
• Publications: 28 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=6.639731E-7).
• BP6: Variant 12-80353462-A-G is Benign according to our data. Variant chr12-80353462-A-G is described in ClinVar as Benign. ClinVar VariationId is 226957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.863 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.5545A>G	p.Ile1849Val	missense_variant	Exon 46 of 59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.5545A>G	p.Ile1849Val	missense_variant	Exon 46 of 59	5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1	c.5410A>G	p.Ile1804Val	missense_variant	Exon 50 of 63			ENSP00000496036.1
OTOGL	ENST00000298820.7	c.844A>G	p.Ile282Val	missense_variant	Exon 7 of 18	5		ENSP00000298820.3

Frequencies

GnomAD3 genomes AF: 0.840 AC: 127676 AN: 152040 Hom.: 53654 Cov.: 32

Gnomad AFR AF: 0.810

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.843

Gnomad ASJ AF: 0.848

Gnomad EAS AF: 0.833

Gnomad SAS AF: 0.885

Gnomad FIN AF: 0.820

Gnomad MID AF: 0.810

Gnomad NFE AF: 0.858

Gnomad OTH AF: 0.843

GnomAD2 exomes AF: 0.842 AC: 192566 AN: 228682 AF XY: 0.846

Gnomad AFR exome AF: 0.806

Gnomad AMR exome AF: 0.792

Gnomad ASJ exome AF: 0.845

Gnomad EAS exome AF: 0.820

Gnomad FIN exome AF: 0.820

Gnomad NFE exome AF: 0.859

Gnomad OTH exome AF: 0.831

GnomAD4 exome AF: 0.853 AC: 1234764 AN: 1447790 Hom.: 527041 Cov.: 47 AF XY: 0.854 AC XY: 613917 AN XY: 718828

African (AFR) AF: 0.804 AC: 26782 AN: 33298

American (AMR) AF: 0.801 AC: 34313 AN: 42852

Ashkenazi Jewish (ASJ) AF: 0.841 AC: 21713 AN: 25816

East Asian (EAS) AF: 0.818 AC: 32194 AN: 39352

South Asian (SAS) AF: 0.884 AC: 73765 AN: 83480

European-Finnish (FIN) AF: 0.826 AC: 43554 AN: 52734

Middle Eastern (MID) AF: 0.789 AC: 4530 AN: 5740

European-Non Finnish (NFE) AF: 0.857 AC: 946941 AN: 1104596

Other (OTH) AF: 0.851 AC: 50972 AN: 59922

GnomAD4 genome AF: 0.839 AC: 127723 AN: 152158 Hom.: 53660 Cov.: 32 AF XY: 0.840 AC XY: 62484 AN XY: 74402

African (AFR) AF: 0.809 AC: 33589 AN: 41510

American (AMR) AF: 0.843 AC: 12887 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.848 AC: 2945 AN: 3472

East Asian (EAS) AF: 0.833 AC: 4290 AN: 5152

South Asian (SAS) AF: 0.885 AC: 4275 AN: 4832

European-Finnish (FIN) AF: 0.820 AC: 8681 AN: 10582

Middle Eastern (MID) AF: 0.810 AC: 238 AN: 294

European-Non Finnish (NFE) AF: 0.858 AC: 58322 AN: 68008

Other (OTH) AF: 0.842 AC: 1774 AN: 2108

Alfa AF: 0.849 Hom.: 192539

Bravo AF: 0.836

TwinsUK AF: 0.850 AC: 3153

ALSPAC AF: 0.862 AC: 3324

ESP6500AA AF: 0.815 AC: 3174

ESP6500EA AF: 0.860 AC: 7138

ExAC AF: 0.840 AC: 101149

Asia WGS AF: 0.856 AC: 2977 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ile1840Val in exon 45 of OTOGL: This variant is not expected to have clinical si gnificance because it has been identified in 18.5% (722/3896) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs7297767). -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	9.7
DANN	Benign	0.84
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.75	T;.;T
MetaRNN	Benign	6.6e-7	T;T;T
MetaSVM	Benign	-0.98	T
PhyloP100		0.98
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.57	.;.;N
REVEL	Benign	0.085
Sift	Benign	0.26	.;.;T
Sift4G	Benign	0.32	.;.;T
Vest4		0.046
MPC		0.022
ClinPred		0.0050	T
GERP RS		0.80
gMVP		0.34
Mutation Taster		=99/1	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: rs7297767; hg19: chr12-80747242; COSMIC: COSV54014797; COSMIC: COSV54014797;