NM_001378609.3:c.4744-6_4744-5dupTT

Variant names:

• chr12-80336781-C-CTT
• rs11300714
• NM_001378609.3:c.4744-6_4744-5dupTT

Variant summary

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

The NM_001378609.3(OTOGL):​c.4744-6_4744-5dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000025 (0 hom.)
  • Failed GnomAD Quality Control
• 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: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• 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 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378609.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	NM_001378609.3	MANE Select	c.4744-6_4744-5dupTT		splice_region intron	N/A	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.4744-6_4744-5dupTT		splice_region intron	N/A	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.4744-6_4744-5dupTT		splice_region intron	N/A	NP_775862.4	Q3ZCN5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.4744-16_4744-15insTT		intron	N/A	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.4609-16_4609-15insTT		intron	N/A	ENSP00000496036.1	A0A2R8YF04
	OTOGL	ENST00000298820.7	TSL:5	c.43-16_43-15insTT		intron	N/A	ENSP00000298820.3	H7BXL6

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 147876 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000148 AC: 11 AN: 74216 AF XY: 0.000177

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000238

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000284

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000139

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000247 AC: 27 AN: 1092888 Hom.: 0 Cov.: 0 AF XY: 0.0000333 AC XY: 18 AN XY: 541102

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

African (AFR) AF: 0.000123 AC: 3 AN: 24470

American (AMR) AF: 0.000175 AC: 5 AN: 28518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19798

East Asian (EAS) AF: 0.00 AC: 0 AN: 26192

South Asian (SAS) AF: 0.0000802 AC: 5 AN: 62340

European-Finnish (FIN) AF: 0.0000268 AC: 1 AN: 37356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4038

European-Non Finnish (NFE) AF: 0.0000154 AC: 13 AN: 844362

Other (OTH) AF: 0.00 AC: 0 AN: 45814

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 147876 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 71990

African (AFR) AF: 0.00 AC: 0 AN: 40502

American (AMR) AF: 0.00 AC: 0 AN: 14840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3402

East Asian (EAS) AF: 0.00 AC: 0 AN: 5056

South Asian (SAS) AF: 0.00 AC: 0 AN: 4700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66612

Other (OTH) AF: 0.00 AC: 0 AN: 2006

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs11300714;

hg19: chr12-80730561;