rs10778725

Positions:

• chr12-80318640-G-A
• chr12-80318640-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378609.3(OTOGL):​c.3729G>A​(p.Pro1243=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.974 in 1,468,996 control chromosomes in the GnomAD database, including 697,666 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70633 hom., cov: 31)
  • Exomes 𝑓: 0.98 (627033 hom.)
• Consequence: OTOGL NM_001378609.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.525

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 12-80318640-G-A is Benign according to our data. Variant chr12-80318640-G-A is described in ClinVar as [Benign]. Clinvar id is 226944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-80318640-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.525 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.3729G>A	p.Pro1243=	synonymous_variant	33/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.3729G>A	p.Pro1243=	synonymous_variant	33/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.3594G>A	p.Pro1198=	synonymous_variant	37/63

Frequencies

GnomAD3 genomes AF: 0.963 AC: 146431 AN: 152102 Hom.: 70575 Cov.: 31

Gnomad AFR AF: 0.955

Gnomad AMI AF: 0.980

Gnomad AMR AF: 0.898

Gnomad ASJ AF: 0.974

Gnomad EAS AF: 0.948

Gnomad SAS AF: 0.938

Gnomad FIN AF: 0.972

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.982

Gnomad OTH AF: 0.972

GnomAD3 exomes AF: 0.949 AC: 99078 AN: 104450 Hom.: 47231 AF XY: 0.952 AC XY: 53608 AN XY: 56340

Gnomad AFR exome AF: 0.945

Gnomad AMR exome AF: 0.817

Gnomad ASJ exome AF: 0.973

Gnomad EAS exome AF: 0.934

Gnomad SAS exome AF: 0.941

Gnomad FIN exome AF: 0.971

Gnomad NFE exome AF: 0.981

Gnomad OTH exome AF: 0.960

GnomAD4 exome AF: 0.976 AC: 1284595 AN: 1316776 Hom.: 627033 Cov.: 43 AF XY: 0.975 AC XY: 631963 AN XY: 648196

Gnomad4 AFR exome AF: 0.954

Gnomad4 AMR exome AF: 0.844

Gnomad4 ASJ exome AF: 0.972

Gnomad4 EAS exome AF: 0.954

Gnomad4 SAS exome AF: 0.944

Gnomad4 FIN exome AF: 0.972

Gnomad4 NFE exome AF: 0.982

Gnomad4 OTH exome AF: 0.973

GnomAD4 genome AF: 0.963 AC: 146548 AN: 152220 Hom.: 70633 Cov.: 31 AF XY: 0.961 AC XY: 71483 AN XY: 74416

Gnomad4 AFR AF: 0.955

Gnomad4 AMR AF: 0.898

Gnomad4 ASJ AF: 0.974

Gnomad4 EAS AF: 0.949

Gnomad4 SAS AF: 0.938

Gnomad4 FIN AF: 0.972

Gnomad4 NFE AF: 0.982

Gnomad4 OTH AF: 0.973

Alfa AF: 0.970 Hom.: 43721

Bravo AF: 0.956

Asia WGS AF: 0.943 AC: 3274 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Pro1234Pro in exon 32 of OTOGL: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 4.5% (160/3556) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs10778725). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.5
DANN	Benign	0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs10778725; hg19: chr12-80712420;