rs145653077

chr12-80355852-G-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.5710G>A(p.Asp1904Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00349 in 1,613,898 control chromosomes in the GnomAD database, including 64 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1904E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0057 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (51 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.29

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=0.009504139).
• BP6: Variant 12-80355852-G-A is Benign according to our data. Variant chr12-80355852-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-80355852-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00571 (869/152258) while in subpopulation NFE AF= 0.00487 (331/68020). AF 95% confidence interval is 0.00443. There are 13 homozygotes in gnomad4. There are 556 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.5710G>A	p.Asp1904Asn	missense_variant	47/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.5710G>A	p.Asp1904Asn	missense_variant	47/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.5575G>A	p.Asp1859Asn	missense_variant	51/63
OTOGL	ENST00000298820.7	c.1012G>A	p.Asp338Asn	missense_variant	8/18	5

Frequencies

GnomAD3 genomes AF: 0.00571 AC: 869 AN: 152140 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0440

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00487

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00568 AC: 1401 AN: 246510 Hom.: 16 AF XY: 0.00535 AC XY: 717 AN XY: 133932

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00255

Gnomad ASJ exome AF: 0.00388

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0388

Gnomad NFE exome AF: 0.00364

Gnomad OTH exome AF: 0.00548

GnomAD4 exome AF: 0.00325 AC: 4756 AN: 1461640 Hom.: 51 Cov.: 31 AF XY: 0.00324 AC XY: 2359 AN XY: 727096

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.00371

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0376

Gnomad4 NFE exome AF: 0.00209

Gnomad4 OTH exome AF: 0.00321

GnomAD4 genome AF: 0.00571 AC: 869 AN: 152258 Hom.: 13 Cov.: 32 AF XY: 0.00747 AC XY: 556 AN XY: 74432

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0440

Gnomad4 NFE AF: 0.00487

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00362 Hom.: 6

Bravo AF: 0.00217

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000259 AC: 1

ESP6500EA AF: 0.00241 AC: 20

ExAC AF: 0.00499 AC: 603

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00172

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 13, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	OTOGL: BP4, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 16, 2015	p.Asp1895Asn in exon 46 of OTOGL: This variant is not expected to have clinical significance because it has been identified in 3.79% (251/6614) of Finnish chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs145653077). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	19
Dann	Benign	0.93
Eigen	Benign	0.12
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T;.;T
MetaRNN	Benign	0.0095	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.31	T
Vest4		0.30
MVP		0.22
MPC		0.041
ClinPred		0.035	T
GERP RS		4.3
gMVP		0.28

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: rs145653077; hg19: chr12-80749632;