rs10778727

chr12-80341991-T-Cchr12-80341991-T-G

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.5094T>C(p.Asn1698=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.61 in 1,605,588 control chromosomes in the GnomAD database, including 306,149 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (22649 hom., cov: 32)
  • Exomes 𝑓: 0.62 (283500 hom.)
• Consequence: OTOGL NM_001378609.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.263

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=-0.51).
• BP6: Variant 12-80341991-T-C is Benign according to our data. Variant chr12-80341991-T-C is described in ClinVar as [Benign]. Clinvar id is 226952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-80341991-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.263 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.5094T>C	p.Asn1698=	synonymous_variant	44/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.5094T>C	p.Asn1698=	synonymous_variant	44/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.4959T>C	p.Asn1653=	synonymous_variant	48/63
OTOGL	ENST00000298820.7	c.396T>C	p.Asn132=	synonymous_variant	5/18	5

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78823 AN: 151906 Hom.: 22649 Cov.: 32

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.479

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.719

Gnomad SAS AF: 0.596

Gnomad FIN AF: 0.683

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.635

Gnomad OTH AF: 0.554

GnomAD3 exomes AF: 0.584 AC: 139845 AN: 239328 Hom.: 42620 AF XY: 0.596 AC XY: 77252 AN XY: 129684

Gnomad AFR exome AF: 0.246

Gnomad AMR exome AF: 0.405

Gnomad ASJ exome AF: 0.625

Gnomad EAS exome AF: 0.709

Gnomad SAS exome AF: 0.606

Gnomad FIN exome AF: 0.687

Gnomad NFE exome AF: 0.637

Gnomad OTH exome AF: 0.590

GnomAD4 exome AF: 0.620 AC: 900538 AN: 1453564 Hom.: 283500 Cov.: 41 AF XY: 0.621 AC XY: 448778 AN XY: 722732

Gnomad4 AFR exome AF: 0.240

Gnomad4 AMR exome AF: 0.415

Gnomad4 ASJ exome AF: 0.620

Gnomad4 EAS exome AF: 0.726

Gnomad4 SAS exome AF: 0.608

Gnomad4 FIN exome AF: 0.687

Gnomad4 NFE exome AF: 0.634

Gnomad4 OTH exome AF: 0.606

GnomAD4 genome AF: 0.519 AC: 78837 AN: 152024 Hom.: 22649 Cov.: 32 AF XY: 0.523 AC XY: 38829 AN XY: 74308

Gnomad4 AFR AF: 0.256

Gnomad4 AMR AF: 0.479

Gnomad4 ASJ AF: 0.629

Gnomad4 EAS AF: 0.718

Gnomad4 SAS AF: 0.596

Gnomad4 FIN AF: 0.683

Gnomad4 NFE AF: 0.635

Gnomad4 OTH AF: 0.555

Alfa AF: 0.611 Hom.: 56165

Bravo AF: 0.488

Asia WGS AF: 0.631 AC: 2192 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Asn1689Asn in exon 43 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 36.2% (2963/8184) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs10778727). -
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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	6.1
Dann	Benign	0.80

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: rs10778727; hg19: chr12-80735771; COSMIC: COSV54014242; COSMIC: COSV54014242;