chr12-80103143-C-G

Variant names:

• chr12-80103143-C-G
• rs10506821
• NM_001378609.3:c.-20+3538C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378609.3(OTOGL):​c.-20+3538C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,180,308 control chromosomes in the GnomAD database, including 326 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.012 (50 hom., cov: 32)
  • Exomes 𝑓: 0.012 (276 hom.)
• Consequence: OTOGL NM_001378609.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.13
• Publications: 7 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

ENSG00000230291 (HGNC:):

RPL26P32 (HGNC:36448):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.-20+3538C>G		intron_variant	Intron 1 of 58	ENST00000547103.7	NP_001365538.2
RPL26P32		n.80103143C>G		intragenic_variant
OTOGL	NM_001378610.3	c.-592+3538C>G		intron_variant	Intron 1 of 61		NP_001365539.2
OTOGL	NM_001368062.3	c.-1032+3538C>G		intron_variant	Intron 1 of 62		NP_001354991.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.-20+3538C>G		intron_variant	Intron 1 of 58	5	NM_001378609.3	ENSP00000447211.2
ENSG00000230291	ENST00000492623.1	n.191G>C		non_coding_transcript_exon_variant	Exon 1 of 1	6
OTOGL	ENST00000646859.1	c.-1032+3538C>G		intron_variant	Intron 1 of 62			ENSP00000496036.1
OTOGL	ENST00000643417.1	n.69+3538C>G		intron_variant	Intron 1 of 22

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1758 AN: 152122 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.00485

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.0295

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00879

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.0120 AC: 12308 AN: 1028068 Hom.: 276 Cov.: 15 AF XY: 0.0119 AC XY: 6318 AN XY: 531080

African (AFR) AF: 0.00114 AC: 30 AN: 26252

American (AMR) AF: 0.00317 AC: 140 AN: 44150

Ashkenazi Jewish (ASJ) AF: 0.0100 AC: 236 AN: 23534

East Asian (EAS) AF: 0.101 AC: 3801 AN: 37608

South Asian (SAS) AF: 0.0101 AC: 781 AN: 77228

European-Finnish (FIN) AF: 0.0281 AC: 1320 AN: 47016

Middle Eastern (MID) AF: 0.00319 AC: 15 AN: 4702

European-Non Finnish (NFE) AF: 0.00747 AC: 5389 AN: 721420

Other (OTH) AF: 0.0129 AC: 596 AN: 46158

GnomAD4 genome AF: 0.0115 AC: 1757 AN: 152240 Hom.: 50 Cov.: 32 AF XY: 0.0127 AC XY: 942 AN XY: 74438

African (AFR) AF: 0.00176 AC: 73 AN: 41538

American (AMR) AF: 0.00484 AC: 74 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3468

East Asian (EAS) AF: 0.107 AC: 555 AN: 5168

South Asian (SAS) AF: 0.0110 AC: 53 AN: 4824

European-Finnish (FIN) AF: 0.0295 AC: 313 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00879 AC: 598 AN: 68022

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.0112 Hom.: 0

Bravo AF: 0.0113

Asia WGS AF: 0.0470 AC: 162 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.7
DANN	Benign	0.44
PhyloP100		3.1

Splicing

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

Other links and lift over

dbSNP: rs10506821; hg19: chr12-80496923; COSMIC: COSV72222960;