rs1551122

chr12-80372020-A-Gchr12-80372020-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378609.3(OTOGL):c.6737A>G(p.Asn2246Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.608 in 1,538,726 control chromosomes in the GnomAD database, including 294,099 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N2246N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.50 (22244 hom., cov: 32)
  • Exomes 𝑓: 0.62 (271855 hom.)
• Consequence: OTOGL NM_001378609.3 missense, splice_region
• Scores: Splicing: ADA: 0.8902
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.50

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=4.559077E-6).
• BP6: Variant 12-80372020-A-G is Benign according to our data. Variant chr12-80372020-A-G is described in ClinVar as [Benign]. Clinvar id is 226972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-80372020-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.704 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.6737A>G	p.Asn2246Ser	missense_variant, splice_region_variant	57/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.6737A>G	p.Asn2246Ser	missense_variant, splice_region_variant	57/59	5	NM_001378609.3	P1

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76353 AN: 151816 Hom.: 22245 Cov.: 32

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.635

Gnomad EAS AF: 0.724

Gnomad SAS AF: 0.626

Gnomad FIN AF: 0.685

Gnomad MID AF: 0.545

Gnomad NFE AF: 0.637

Gnomad OTH AF: 0.545

GnomAD3 exomes AF: 0.581 AC: 122147 AN: 210322 Hom.: 37632 AF XY: 0.597 AC XY: 68609 AN XY: 114888

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.383

Gnomad ASJ exome AF: 0.633

Gnomad EAS exome AF: 0.697

Gnomad SAS exome AF: 0.630

Gnomad FIN exome AF: 0.686

Gnomad NFE exome AF: 0.636

Gnomad OTH exome AF: 0.589

GnomAD4 exome AF: 0.619 AC: 859074 AN: 1386792 Hom.: 271855 Cov.: 28 AF XY: 0.622 AC XY: 429197 AN XY: 690076

Gnomad4 AFR exome AF: 0.170

Gnomad4 AMR exome AF: 0.405

Gnomad4 ASJ exome AF: 0.628

Gnomad4 EAS exome AF: 0.725

Gnomad4 SAS exome AF: 0.633

Gnomad4 FIN exome AF: 0.684

Gnomad4 NFE exome AF: 0.634

Gnomad4 OTH exome AF: 0.603

GnomAD4 genome AF: 0.503 AC: 76365 AN: 151934 Hom.: 22244 Cov.: 32 AF XY: 0.508 AC XY: 37717 AN XY: 74270

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.474

Gnomad4 ASJ AF: 0.635

Gnomad4 EAS AF: 0.724

Gnomad4 SAS AF: 0.626

Gnomad4 FIN AF: 0.685

Gnomad4 NFE AF: 0.637

Gnomad4 OTH AF: 0.546

Alfa AF: 0.620 Hom.: 51395

Bravo AF: 0.469

TwinsUK AF: 0.640 AC: 2372

ALSPAC AF: 0.641 AC: 2470

ESP6500AA AF: 0.215 AC: 948

ESP6500EA AF: 0.641 AC: 5509

ExAC AF: 0.584 AC: 70865

Asia WGS AF: 0.639 AC: 2207 AN: 3452

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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	Nov 24, 2014	Asn2237Ser in exon 56 of OTOGL: This variant is not expected to have clinical si gnificance because it has been identified in 35.9% (3089/8598) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs1551122). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.77	T;.;T
MetaRNN	Benign	0.0000046	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.56	P;P;P
PrimateAI	Uncertain	0.52	T
Vest4		0.17
MPC		0.17
ClinPred		0.021	T
GERP RS		6.0
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.89
dbscSNV1_RF	Benign	0.30
SpliceAI score (max)		0.16		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: rs1551122; hg19: chr12-80765800; COSMIC: COSV54014277; COSMIC: COSV54014277;