rs79120261

Variant names:

• chr12-80352288-T-C
• rs79120261
• NM_001378609.3:c.5266-7T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378609.3(OTOGL):​c.5266-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 1,602,594 control chromosomes in the GnomAD database, including 809 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (56 hom., cov: 33)
  • Exomes 𝑓: 0.029 (753 hom.)
• Consequence: OTOGL NM_001378609.3 splice_region, intron
• Scores: Splicing: ADA: 0.0004058
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.90
• Publications: 3 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=-0.76).
• BP6: Variant 12-80352288-T-C is Benign according to our data. Variant chr12-80352288-T-C is described in ClinVar as Benign. ClinVar VariationId is 226954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0205 (3123/152284) while in subpopulation NFE AF = 0.0319 (2170/68008). AF 95% confidence interval is 0.0308. There are 56 homozygotes in GnomAd4. There are 1429 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 56 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.5266-7T>C		splice_region_variant, intron_variant	Intron 44 of 58	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.5266-7T>C		splice_region_variant, intron_variant	Intron 44 of 58	5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1	c.5131-7T>C		splice_region_variant, intron_variant	Intron 48 of 62			ENSP00000496036.1
OTOGL	ENST00000298820.7	c.565-7T>C		splice_region_variant, intron_variant	Intron 5 of 17	5		ENSP00000298820.3

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3122 AN: 152166 Hom.: 55 Cov.: 33

Gnomad AFR AF: 0.00649

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0286

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.00754

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0319

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.0196 AC: 4609 AN: 235408 AF XY: 0.0202

Gnomad AFR exome AF: 0.00601

Gnomad AMR exome AF: 0.0155

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.000115

Gnomad FIN exome AF: 0.00737

Gnomad NFE exome AF: 0.0317

Gnomad OTH exome AF: 0.0256

GnomAD4 exome AF: 0.0292 AC: 42280 AN: 1450310 Hom.: 753 Cov.: 30 AF XY: 0.0287 AC XY: 20672 AN XY: 721204

African (AFR) AF: 0.00638 AC: 210 AN: 32900

American (AMR) AF: 0.0165 AC: 694 AN: 42118

Ashkenazi Jewish (ASJ) AF: 0.0195 AC: 499 AN: 25550

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39518

South Asian (SAS) AF: 0.00511 AC: 428 AN: 83814

European-Finnish (FIN) AF: 0.00711 AC: 378 AN: 53142

Middle Eastern (MID) AF: 0.0388 AC: 221 AN: 5696

European-Non Finnish (NFE) AF: 0.0346 AC: 38306 AN: 1107682

Other (OTH) AF: 0.0257 AC: 1542 AN: 59890

GnomAD4 genome AF: 0.0205 AC: 3123 AN: 152284 Hom.: 56 Cov.: 33 AF XY: 0.0192 AC XY: 1429 AN XY: 74462

African (AFR) AF: 0.00654 AC: 272 AN: 41574

American (AMR) AF: 0.0285 AC: 436 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4828

European-Finnish (FIN) AF: 0.00754 AC: 80 AN: 10616

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0319 AC: 2170 AN: 68008

Other (OTH) AF: 0.0218 AC: 46 AN: 2112

Alfa AF: 0.0281 Hom.: 32

Bravo AF: 0.0214

Asia WGS AF: 0.00433 AC: 15 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 27, 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

- -

Jul 31, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

5239-7T>C in intron 43 of OTOGL: This variant is not expected to have clinical s ignificance because it has been identified in 3.3% (268/8158) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs79120261). -

Sep 08, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	13
DANN	Benign	0.66
PhyloP100		2.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00041
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.070		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: rs79120261; hg19: chr12-80746068;