chr12-80209493-TG-T

Position:

• chr12-80209493-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001378609.3(OTOGL):​c.63del​(p.Leu22CysfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000614 in 1,497,204 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: OTOGL NM_001378609.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.35

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 53 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-80209493-TG-T is Pathogenic according to our data. Variant chr12-80209493-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 817079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.63del	p.Leu22CysfsTer14	frameshift_variant	2/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.63del	p.Leu22CysfsTer14	frameshift_variant	2/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.63del	p.Leu22CysfsTer14	frameshift_variant	7/63
OTOGL	ENST00000643417.1	n.723del		non_coding_transcript_exon_variant	5/23

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000763 AC: 1 AN: 131040 Hom.: 0 AF XY: 0.0000140 AC XY: 1 AN XY: 71444

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000195

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000639 AC: 86 AN: 1344882 Hom.: 0 Cov.: 25 AF XY: 0.0000466 AC XY: 31 AN XY: 665052

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000286

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000793

Gnomad4 OTH exome AF: 0.0000354

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74478

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000114 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 08, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 817079). This variant has not been reported in the literature in individuals affected with OTOGL-related conditions. This variant is present in population databases (rs376104832, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Leu13Cysfs*14) in the OTOGL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOGL are known to be pathogenic (PMID: 23122586). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2018	The c.36delG variant in the OTOGL gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.36delG variant causes a frameshift starting with codon Leucine 13, changes this amino acid to a Cysteine residue, and creates a premature Stop codon at position 14 of the new reading frame, denoted p.Leu13CysfsX14. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.36delG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.36delG as a likely pathogenic variant. -

Autosomal recessive nonsyndromic hearing loss 84B Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 09, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs376104832; hg19: chr12-80603273;