12-80336781-CTTT-CTTTTTT

Variant names:

• chr12-80336781-C-CTTT
• rs11300714
• NM_001378609.3:c.4744-7_4744-5dupTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001378609.3(OTOGL):​c.4744-7_4744-5dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,093,664 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: OTOGL NM_001378609.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.465
• 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: Uncertain_significance. The variant received 2 ACMG points.

• 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.4744-7_4744-5dupTTT		splice_region_variant, intron_variant	Intron 40 of 58	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.4744-16_4744-15insTTT		intron_variant	Intron 40 of 58	5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1	c.4609-16_4609-15insTTT		intron_variant	Intron 44 of 62			ENSP00000496036.1
OTOGL	ENST00000298820.7	c.43-16_43-15insTTT		intron_variant	Intron 1 of 17	5		ENSP00000298820.3

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1093664 Hom.: 0 Cov.: 0 AF XY: 0.00000369 AC XY: 2 AN XY: 541492

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

African (AFR) AF: 0.00 AC: 0 AN: 24494

American (AMR) AF: 0.00 AC: 0 AN: 28556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19810

East Asian (EAS) AF: 0.00 AC: 0 AN: 26202

South Asian (SAS) AF: 0.0000160 AC: 1 AN: 62410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4040

European-Non Finnish (NFE) AF: 0.00000118 AC: 1 AN: 844940

Other (OTH) AF: 0.00 AC: 0 AN: 45834

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.47

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11300714; hg19: chr12-80730561;