12-80336781-CTTT-CTTTT

Variant names:

• chr12-80336781-C-CT
• rs11300714
• NM_001378609.3:c.4744-5dupT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_001378609.3(OTOGL):​c.4744-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 1,107,664 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (1 hom., cov: 26)
  • Exomes 𝑓: 0.021 (0 hom.)
• Consequence: OTOGL NM_001378609.3 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.465
• Publications: 2 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 0 ACMG points.

• PM2: Variant has high frequency in the EAS (0.0248) population. However there is too low homozygotes in high coverage region: (expected more than 90, got 1).
• BP6: Variant 12-80336781-C-CT is Benign according to our data. Variant chr12-80336781-C-CT is described in ClinVar as Benign. ClinVar VariationId is 1987155.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.4744-5dupT		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_4744-15insT		intron_variant	Intron 40 of 58	5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1	c.4609-16_4609-15insT		intron_variant	Intron 44 of 62			ENSP00000496036.1
OTOGL	ENST00000298820.7	c.43-16_43-15insT		intron_variant	Intron 1 of 17	5		ENSP00000298820.3

Frequencies

GnomAD3 genomes AF: 0.000298 AC: 44 AN: 147824 Hom.: 1 Cov.: 26

Gnomad AFR AF: 0.000272

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000404

Gnomad ASJ AF: 0.000294

Gnomad EAS AF: 0.000791

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00115

Gnomad MID AF: 0.00993

Gnomad NFE AF: 0.000120

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0315 AC: 2336 AN: 74216 AF XY: 0.0308

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.0385

Gnomad ASJ exome AF: 0.0365

Gnomad EAS exome AF: 0.0542

Gnomad FIN exome AF: 0.0265

Gnomad NFE exome AF: 0.0283

Gnomad OTH exome AF: 0.0277

GnomAD4 exome AF: 0.0208 AC: 19939 AN: 959764 Hom.: 0 Cov.: 0 AF XY: 0.0204 AC XY: 9680 AN XY: 473672

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

African (AFR) AF: 0.0206 AC: 448 AN: 21700

American (AMR) AF: 0.0239 AC: 615 AN: 25700

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 393 AN: 17218

East Asian (EAS) AF: 0.0267 AC: 520 AN: 19492

South Asian (SAS) AF: 0.0222 AC: 1227 AN: 55364

European-Finnish (FIN) AF: 0.0189 AC: 593 AN: 31436

Middle Eastern (MID) AF: 0.0150 AC: 55 AN: 3672

European-Non Finnish (NFE) AF: 0.0204 AC: 15194 AN: 745360

Other (OTH) AF: 0.0224 AC: 894 AN: 39822

⚠️ 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 AF: 0.000304 AC: 45 AN: 147900 Hom.: 1 Cov.: 26 AF XY: 0.000361 AC XY: 26 AN XY: 72046

African (AFR) AF: 0.000296 AC: 12 AN: 40596

American (AMR) AF: 0.000404 AC: 6 AN: 14856

Ashkenazi Jewish (ASJ) AF: 0.000294 AC: 1 AN: 3402

East Asian (EAS) AF: 0.000793 AC: 4 AN: 5042

South Asian (SAS) AF: 0.00 AC: 0 AN: 4686

European-Finnish (FIN) AF: 0.00115 AC: 11 AN: 9538

Middle Eastern (MID) AF: 0.0107 AC: 3 AN: 280

European-Non Finnish (NFE) AF: 0.000120 AC: 8 AN: 66584

Other (OTH) AF: 0.00 AC: 0 AN: 2016

Alfa AF: 0.00 Hom.: 104

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs11300714; hg19: chr12-80730561;