rs9783425

Positions:

• chr12-80267247-G-A
• chr12-80267247-G-C
• chr12-80267247-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378609.3(OTOGL):​c.2391-6G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,513,180 control chromosomes in the GnomAD database, including 1,321 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 0.054 (720 hom., cov: 31)
  • Exomes 𝑓: 0.0054 (601 hom.)
• Consequence: OTOGL NM_001378609.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004326
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.66

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 (BayesDel_noAF=-0.83).
• BP6: Variant 12-80267247-G-A is Benign according to our data. Variant chr12-80267247-G-A is described in ClinVar as [Benign]. Clinvar id is 226932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.2391-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.2391-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.2391-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.0542 AC: 8217 AN: 151596 Hom.: 716 Cov.: 31

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.000573

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.0378

GnomAD3 exomes AF: 0.0123 AC: 2279 AN: 185720 Hom.: 183 AF XY: 0.00934 AC XY: 928 AN XY: 99372

Gnomad AFR exome AF: 0.177

Gnomad AMR exome AF: 0.00833

Gnomad ASJ exome AF: 0.000113

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000297

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000616

Gnomad OTH exome AF: 0.00632

GnomAD4 exome AF: 0.00543 AC: 7389 AN: 1361472 Hom.: 601 Cov.: 28 AF XY: 0.00467 AC XY: 3157 AN XY: 676106

Gnomad4 AFR exome AF: 0.193

Gnomad4 AMR exome AF: 0.00983

Gnomad4 ASJ exome AF: 0.0000406

Gnomad4 EAS exome AF: 0.0000269

Gnomad4 SAS exome AF: 0.000450

Gnomad4 FIN exome AF: 0.000237

Gnomad4 NFE exome AF: 0.000327

Gnomad4 OTH exome AF: 0.0122

GnomAD4 genome AF: 0.0543 AC: 8235 AN: 151708 Hom.: 720 Cov.: 31 AF XY: 0.0516 AC XY: 3824 AN XY: 74112

Gnomad4 AFR AF: 0.190

Gnomad4 AMR AF: 0.0166

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000573

Gnomad4 NFE AF: 0.000663

Gnomad4 OTH AF: 0.0374

Alfa AF: 0.0187 Hom.: 102

Bravo AF: 0.0628

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	2364-6G>A in intron 20 of OTOGL: This variant is not expected to have clinical s ignificance because it has been identified in 18.5% (678/3662) of African Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs9783425). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2017	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.7
DANN	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000043
dbscSNV1_RF	Benign	0.0020
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: rs9783425; hg19: chr12-80661027;