NM_001378609.3:c.39G>A

Variant names:

• chr12-80209470-G-A
• rs1191512072
• NM_001378609.3:c.39G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001378609.3(OTOGL):​c.39G>A​(p.Trp13*) 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
• Publications: 0 publications found

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]

OTOGL Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 84B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 80 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 rank	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.39G>A	p.Trp13*	stop_gained	Exon 2 of 59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.39G>A	p.Trp13*	stop_gained	Exon 2 of 59	5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1	c.39G>A	p.Trp13*	stop_gained	Exon 7 of 63			ENSP00000496036.1
OTOGL	ENST00000643417.1	n.699G>A		non_coding_transcript_exon_variant	Exon 5 of 23

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000763 AC: 1 AN: 131090 AF XY: 0.00

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 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

African (AFR) AF: 0.0000321 AC: 1 AN: 31170

American (AMR) AF: 0.00 AC: 0 AN: 34976

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24706

East Asian (EAS) AF: 0.00 AC: 0 AN: 35404

South Asian (SAS) AF: 0.00 AC: 0 AN: 76384

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5628

European-Non Finnish (NFE) AF: 0.0000169 AC: 18 AN: 1064104

Other (OTH) AF: 0.00 AC: 0 AN: 56976

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

Apr 10, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		7.0
Vest4		0.36
GERP RS		5.6
Mutation Taster		=6/194	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1191512072; hg19: chr12-80603250;