rs61729710

Positions:

• chr12-80342124-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378609.3(OTOGL):​c.5227T>A​(p.Leu1743Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000623 in 1,595,370 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.633

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009636909).
• BP6: Variant 12-80342124-T-A is Benign according to our data. Variant chr12-80342124-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 226953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00329 (501/152300) while in subpopulation AFR AF= 0.0114 (473/41564). AF 95% confidence interval is 0.0105. There are 3 homozygotes in gnomad4. There are 234 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.5227T>A	p.Leu1743Ile	missense_variant	44/59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.5227T>A	p.Leu1743Ile	missense_variant	44/59	5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1	c.5092T>A	p.Leu1698Ile	missense_variant	48/63			ENSP00000496036.1
OTOGL	ENST00000298820.7	c.526T>A	p.Leu176Ile	missense_variant	5/18	5		ENSP00000298820.3

Frequencies

GnomAD3 genomes AF: 0.00328 AC: 499 AN: 152182 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000833 AC: 180 AN: 216076 Hom.: 1 AF XY: 0.000714 AC XY: 83 AN XY: 116188

Gnomad AFR exome AF: 0.0111

Gnomad AMR exome AF: 0.000547

Gnomad ASJ exome AF: 0.000107

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000375

Gnomad FIN exome AF: 0.0000493

Gnomad NFE exome AF: 0.0000854

Gnomad OTH exome AF: 0.000551

GnomAD4 exome AF: 0.000342 AC: 493 AN: 1443070 Hom.: 1 Cov.: 32 AF XY: 0.000321 AC XY: 230 AN XY: 715812

Gnomad4 AFR exome AF: 0.00915

Gnomad4 AMR exome AF: 0.000712

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.000209

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.000553

GnomAD4 genome AF: 0.00329 AC: 501 AN: 152300 Hom.: 3 Cov.: 32 AF XY: 0.00314 AC XY: 234 AN XY: 74468

Gnomad4 AFR AF: 0.0114

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000536 Hom.: 1

Bravo AF: 0.00361

ESP6500AA AF: 0.0101 AC: 37

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000987 AC: 119

Asia WGS AF: 0.000289 AC: 1 AN: 3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	OTOGL: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Leu1734Ile in exon 43 of OTOGL: This variant is not expected to have clinical si gnificance because it has been identified in 1.0% (37/3654) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs61729710). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	13
DANN	Uncertain	0.99
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.70	T;.;T
MetaRNN	Benign	0.0096	T;T;T
MetaSVM	Benign	-0.61	T
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.5	.;.;N
REVEL	Uncertain	0.39
Sift	Benign	0.26	.;.;T
Sift4G	Uncertain	0.022	.;.;D
Vest4		0.42
MVP		0.36
MPC		0.18
ClinPred		0.013	T
GERP RS		2.6
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs61729710; hg19: chr12-80735904;