rs202085918

chr12-80313513-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3 BP4_Moderate BP6 BS1

The NM_001378609.3(OTOGL):c.3488A>G(p.Asp1163Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,612,464 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1163E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (7 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 8.84

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 Likely_benign. Variant got -6 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: BayesDel_noAF, Cadd, FATHMM_MKL, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.10103613).
• BP6: Variant 12-80313513-A-G is Benign according to our data. Variant chr12-80313513-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 500879.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00222 (3239/1460346) while in subpopulation NFE AF= 0.00263 (2926/1110810). AF 95% confidence interval is 0.00255. There are 7 homozygotes in gnomad4_exome. There are 1580 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.3488A>G	p.Asp1163Gly	missense_variant	31/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.3488A>G	p.Asp1163Gly	missense_variant	31/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.3353A>G	p.Asp1118Gly	missense_variant	35/63

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 267 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00603

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00244

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00188 AC: 463 AN: 246684 Hom.: 1 AF XY: 0.00207 AC XY: 277 AN XY: 134000

Gnomad AFR exome AF: 0.000128

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00219

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00325

Gnomad NFE exome AF: 0.00313

Gnomad OTH exome AF: 0.000995

GnomAD4 exome AF: 0.00222 AC: 3239 AN: 1460346 Hom.: 7 Cov.: 31 AF XY: 0.00217 AC XY: 1580 AN XY: 726546

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00275

Gnomad4 NFE exome AF: 0.00263

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00176 AC: 267 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.00202 AC XY: 150 AN XY: 74312

Gnomad4 AFR AF: 0.000483

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00603

Gnomad4 NFE AF: 0.00244

Gnomad4 OTH AF: 0.00239

Alfa AF: 0.00220 Hom.: 0

Bravo AF: 0.00118

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000230 AC: 1

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00227 AC: 275

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2021	Has not been previously reported in association with hearing loss to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23486545) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 05, 2024	- -

Autosomal recessive nonsyndromic hearing loss 84B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 16, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 25, 2017

p.Asp1154Gly in exon 30 of OTOGL: This variant is not expected to have clinical significance because it has been identified in 0.3% (408/124060) of European chr omosomes including 1 homozygote by the Genome Aggregation Database (gnomAD, http ://gnomad.broadinstitute.org; dbSNP rs202085918). -

OTOGL-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 22, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;.;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Uncertain	0.62	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
Vest4		0.96
MVP		0.67
MPC		0.20
ClinPred		0.12	T
GERP RS		5.8
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs202085918; hg19: chr12-80707293; COSMIC: COSV101509570;