12-80302793-C-T

Position:

• chr12-80302793-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001378609.3(OTOGL):​c.3213+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,455,036 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (17 hom.)
• Consequence: OTOGL NM_001378609.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.675

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-80302793-C-T is Benign according to our data. Variant chr12-80302793-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 499957.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.3213+10C>T		intron_variant		ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.3213+10C>T		intron_variant		5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1	c.3078+10C>T		intron_variant				ENSP00000496036.1

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 202 AN: 152092 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.0406

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00244 AC: 311 AN: 127374 Hom.: 4 AF XY: 0.00204 AC XY: 142 AN XY: 69608

Gnomad AFR exome AF: 0.000106

Gnomad AMR exome AF: 0.000309

Gnomad ASJ exome AF: 0.0440

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000687

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000854

Gnomad OTH exome AF: 0.00290

GnomAD4 exome AF: 0.00108 AC: 1407 AN: 1302826 Hom.: 17 Cov.: 29 AF XY: 0.00106 AC XY: 678 AN XY: 639978

Gnomad4 AFR exome AF: 0.000106

Gnomad4 AMR exome AF: 0.000250

Gnomad4 ASJ exome AF: 0.0364

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000483

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000440

Gnomad4 OTH exome AF: 0.00317

GnomAD4 genome AF: 0.00133 AC: 202 AN: 152210 Hom.: 2 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74422

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.0406

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00663 Hom.: 3

Bravo AF: 0.00147

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 25, 2023	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	3186+10C>T in intron 27 of OTOGL: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence. It has been identified in 0.2% (20/8178) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu/EVS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.3
DANN	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201373228; hg19: chr12-80696573;