12-80302644-GT-G

Variant names:

• chr12-80302644-GT-G
• rs764178233
• NM_001378609.3:c.3081delT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001378609.3(OTOGL):​c.3081delT​(p.Leu1028TrpfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 1,215,696 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000066 (0 hom.)
• Consequence: OTOGL NM_001378609.3 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.456
• 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 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.3081delT	p.Leu1028TrpfsTer16	frameshift_variant	Exon 28 of 59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.3081delT	p.Leu1028TrpfsTer16	frameshift_variant	Exon 28 of 59	5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1	c.2946delT	p.Leu983TrpfsTer16	frameshift_variant	Exon 32 of 63			ENSP00000496036.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000658 AC: 8 AN: 1215696 Hom.: 0 Cov.: 29 AF XY: 0.00000680 AC XY: 4 AN XY: 588614

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000386 AC: 1 AN: 25910

American (AMR) AF: 0.0000644 AC: 1 AN: 15520

Ashkenazi Jewish (ASJ) AF: 0.0000510 AC: 1 AN: 19594

East Asian (EAS) AF: 0.0000312 AC: 1 AN: 32046

South Asian (SAS) AF: 0.0000201 AC: 1 AN: 49704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3856

European-Non Finnish (NFE) AF: 0.00000303 AC: 3 AN: 988834

Other (OTH) AF: 0.00 AC: 0 AN: 49780

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		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

Other links and lift over

dbSNP: rs764178233; hg19: chr12-80696424;