12-80209470-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001378609.3(OTOGL):c.39G>A(p.Trp13Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000139 in 1,362,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: OTOGL NM_001378609.3 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.99

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 12 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 52 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-80209470-G-A is Pathogenic according to our data. Variant chr12-80209470-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 667385.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.39G>A	p.Trp13Ter	stop_gained	2/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.39G>A	p.Trp13Ter	stop_gained	2/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.39G>A	p.Trp13Ter	stop_gained	7/63
OTOGL	ENST00000643417.1	n.699G>A		non_coding_transcript_exon_variant	5/23

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000763 AC: 1 AN: 131090 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 71468

Gnomad AFR exome AF: 0.000158

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000139 AC: 19 AN: 1362508 Hom.: 0 Cov.: 28 AF XY: 0.0000178 AC XY: 12 AN XY: 672434

Gnomad4 AFR exome AF: 0.0000321

Gnomad4 AMR exome AF: 0.00

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: 0.0000169

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 10, 2018

The p.Trp4X variant in OTOGL has been identified in a compound heterozygous stat e in 1 individual with hearing loss, who also carried an additional loss-of-func tion variant in OTOGL (LMM data). It has also been identified in 1/6086 African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinsti tute.org; dbSNP rs1191512072), which is low enough to be consistent with a reces sive carrier frequency. This nonsense variant leads to a premature termination c odon at position 4, which is predicted to lead to a truncated or absent protein. Loss of function of the OTOGL gene is an established disease mechanism in autos omal recessive hearing loss. In summary, although additional studies are require d to fully establish its clinical significance, the p.Trp4X variant is likely pa thogenic. ACMG/AMP Criteria applied: PVS1; PM2_Supporting; PM3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	37
Dann	Uncertain	0.99
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A
Vest4		0.36
GERP RS		5.6

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: rs1191512072; hg19: chr12-80603250;