rs183555119

chr12-80352336-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001378609.3(OTOGL):c.5307T>C(p.Tyr1769=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,612,054 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (12 hom.)
• Consequence: OTOGL NM_001378609.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.215

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=-0.55).
• BP6: Variant 12-80352336-T-C is Benign according to our data. Variant chr12-80352336-T-C is described in ClinVar as [Benign]. Clinvar id is 226955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-80352336-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.215 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00219 (334/152326) while in subpopulation NFE AF= 0.00297 (202/68022). AF 95% confidence interval is 0.00263. There are 2 homozygotes in gnomad4. There are 164 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.5307T>C	p.Tyr1769=	synonymous_variant	45/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.5307T>C	p.Tyr1769=	synonymous_variant	45/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.5172T>C	p.Tyr1724=	synonymous_variant	49/63
OTOGL	ENST00000298820.7	c.609T>C	p.Tyr203=	synonymous_variant	6/18	5

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 334 AN: 152208 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00885

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00297

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00302 AC: 739 AN: 244414 Hom.: 4 AF XY: 0.00310 AC XY: 412 AN XY: 132772

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000971

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000699

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.00395

Gnomad OTH exome AF: 0.00451

GnomAD4 exome AF: 0.00281 AC: 4100 AN: 1459728 Hom.: 12 Cov.: 31 AF XY: 0.00285 AC XY: 2068 AN XY: 726050

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000924

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000630

Gnomad4 FIN exome AF: 0.0110

Gnomad4 NFE exome AF: 0.00294

Gnomad4 OTH exome AF: 0.00227

GnomAD4 genome AF: 0.00219 AC: 334 AN: 152326 Hom.: 2 Cov.: 33 AF XY: 0.00220 AC XY: 164 AN XY: 74486

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00885

Gnomad4 NFE AF: 0.00297

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00267 Hom.: 0

Bravo AF: 0.00165

EpiCase AF: 0.00224

EpiControl AF: 0.00214

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Tyr1760Tyr in exon 44 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 0.3% (21/8212) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs183555119). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	2.7
Dann	Benign	0.46

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: rs183555119; hg19: chr12-80746116;