12-80278284-A-G

Variant names:

• chr12-80278284-A-G
• rs1376384
• NM_001378609.3:c.2789+9A>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.2789+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.682 in 1,494,294 control chromosomes in the GnomAD database, including 352,656 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (32393 hom., cov: 32)
  • Exomes 𝑓: 0.69 (320263 hom.)
• Consequence: OTOGL NM_001378609.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.220
• Publications: 14 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 (BayesDel_noAF=-0.55).
• BP6: Variant 12-80278284-A-G is Benign according to our data. Variant chr12-80278284-A-G is described in ClinVar as Benign. ClinVar VariationId is 226934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.915 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378609.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	NM_001378609.3	MANE Select	c.2789+9A>G		intron	N/A	NP_001365538.2
	OTOGL	NM_001378610.3		c.2789+9A>G		intron	N/A	NP_001365539.2
	OTOGL	NM_173591.7		c.2789+9A>G		intron	N/A	NP_775862.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.2789+9A>G		intron	N/A	ENSP00000447211.2
	OTOGL	ENST00000646859.1		c.2789+9A>G		intron	N/A	ENSP00000496036.1

Frequencies

GnomAD3 genomes AF: 0.641 AC: 96810 AN: 151072 Hom.: 32373 Cov.: 32

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.580

Gnomad AMR AF: 0.734

Gnomad ASJ AF: 0.680

Gnomad EAS AF: 0.937

Gnomad SAS AF: 0.697

Gnomad FIN AF: 0.818

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.680

Gnomad OTH AF: 0.667

GnomAD2 exomes AF: 0.726 AC: 103385 AN: 142410 AF XY: 0.719

Gnomad AFR exome AF: 0.447

Gnomad AMR exome AF: 0.807

Gnomad ASJ exome AF: 0.674

Gnomad EAS exome AF: 0.934

Gnomad FIN exome AF: 0.818

Gnomad NFE exome AF: 0.675

Gnomad OTH exome AF: 0.693

GnomAD4 exome AF: 0.686 AC: 921933 AN: 1343104 Hom.: 320263 Cov.: 24 AF XY: 0.687 AC XY: 456073 AN XY: 664176

African (AFR) AF: 0.442 AC: 13259 AN: 30026

American (AMR) AF: 0.797 AC: 27710 AN: 34750

Ashkenazi Jewish (ASJ) AF: 0.672 AC: 16493 AN: 24546

East Asian (EAS) AF: 0.963 AC: 34100 AN: 35402

South Asian (SAS) AF: 0.694 AC: 52928 AN: 76264

European-Finnish (FIN) AF: 0.810 AC: 38868 AN: 47994

Middle Eastern (MID) AF: 0.614 AC: 3418 AN: 5564

European-Non Finnish (NFE) AF: 0.675 AC: 696707 AN: 1032506

Other (OTH) AF: 0.686 AC: 38450 AN: 56052

GnomAD4 genome AF: 0.641 AC: 96875 AN: 151190 Hom.: 32393 Cov.: 32 AF XY: 0.651 AC XY: 48071 AN XY: 73894

African (AFR) AF: 0.450 AC: 18582 AN: 41330

American (AMR) AF: 0.735 AC: 11109 AN: 15120

Ashkenazi Jewish (ASJ) AF: 0.680 AC: 2350 AN: 3454

East Asian (EAS) AF: 0.937 AC: 4818 AN: 5144

South Asian (SAS) AF: 0.697 AC: 3355 AN: 4816

European-Finnish (FIN) AF: 0.818 AC: 8652 AN: 10578

Middle Eastern (MID) AF: 0.677 AC: 199 AN: 294

European-Non Finnish (NFE) AF: 0.680 AC: 45875 AN: 67444

Other (OTH) AF: 0.670 AC: 1407 AN: 2100

Alfa AF: 0.664 Hom.: 59049

Bravo AF: 0.626

Asia WGS AF: 0.807 AC: 2806 AN: 3478

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.

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

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

c.2762+9A>G in intron 24 of OTOGL: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus se quence. It has been identified in 98.3% (175/178) of Japanese chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov/proje cts/SNP; dbSNP rs1376384).

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.0
DANN	Benign	0.82
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1376384; hg19: chr12-80672064;