rs73139245

chr12-80356818-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.5923T>C(p.Leu1975=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0054 in 1,593,886 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (28 hom.)
• Consequence: OTOGL NM_001378609.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0700

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=-0.8).
• BP6: Variant 12-80356818-T-C is Benign according to our data. Variant chr12-80356818-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 226961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00522 (794/152224) while in subpopulation NFE AF= 0.00766 (521/68010). AF 95% confidence interval is 0.00712. There are 5 homozygotes in gnomad4. There are 428 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.5923T>C	p.Leu1975=	synonymous_variant	49/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.5923T>C	p.Leu1975=	synonymous_variant	49/59	5	NM_001378609.3	P1

Frequencies

GnomAD3 genomes AF: 0.00523 AC: 795 AN: 152106 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0199

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00767

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00566 AC: 1318 AN: 232748 Hom.: 4 AF XY: 0.00576 AC XY: 727 AN XY: 126226

Gnomad AFR exome AF: 0.000837

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00126

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0169

Gnomad NFE exome AF: 0.00824

Gnomad OTH exome AF: 0.00537

GnomAD4 exome AF: 0.00542 AC: 7814 AN: 1441662 Hom.: 28 Cov.: 29 AF XY: 0.00544 AC XY: 3896 AN XY: 716728

Gnomad4 AFR exome AF: 0.000768

Gnomad4 AMR exome AF: 0.00113

Gnomad4 ASJ exome AF: 0.00106

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000366

Gnomad4 FIN exome AF: 0.0144

Gnomad4 NFE exome AF: 0.00608

Gnomad4 OTH exome AF: 0.00405

GnomAD4 genome AF: 0.00522 AC: 794 AN: 152224 Hom.: 5 Cov.: 32 AF XY: 0.00575 AC XY: 428 AN XY: 74420

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0199

Gnomad4 NFE AF: 0.00766

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00556 Hom.: 2

Bravo AF: 0.00345

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	OTOGL: BP4, BP7, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Leu1966Leu in exon 48 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 0.5% (44/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs73139245). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	2.1
Dann	Benign	0.68

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: rs73139245; hg19: chr12-80750598; COSMIC: COSV54024860; COSMIC: COSV54024860;