rs61735664

Positions:

• chr12-80341957-A-G

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.5060A>G​(p.Asn1687Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0483 in 1,600,182 control chromosomes in the GnomAD database, including 2,220 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (158 hom., cov: 32)
  • Exomes 𝑓: 0.050 (2062 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.16

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=0.0050604045).
• BP6: Variant 12-80341957-A-G is Benign according to our data. Variant chr12-80341957-A-G is described in ClinVar as [Benign]. Clinvar id is 226950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-80341957-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.5060A>G	p.Asn1687Ser	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.5060A>G	p.Asn1687Ser	missense_variant	44/59	5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1	c.4925A>G	p.Asn1642Ser	missense_variant	48/63			ENSP00000496036.1
OTOGL	ENST00000298820.7	c.359A>G	p.Asn120Ser	missense_variant	5/18	5		ENSP00000298820.3

Frequencies

GnomAD3 genomes AF: 0.0360 AC: 5482 AN: 152164 Hom.: 159 Cov.: 32

Gnomad AFR AF: 0.00997

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0549

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.0541

Gnomad OTH AF: 0.0488

GnomAD3 exomes AF: 0.0370 AC: 8624 AN: 233194 Hom.: 220 AF XY: 0.0373 AC XY: 4701 AN XY: 125920

Gnomad AFR exome AF: 0.00880

Gnomad AMR exome AF: 0.0378

Gnomad ASJ exome AF: 0.0488

Gnomad EAS exome AF: 0.000116

Gnomad SAS exome AF: 0.0185

Gnomad FIN exome AF: 0.0155

Gnomad NFE exome AF: 0.0545

Gnomad OTH exome AF: 0.0498

GnomAD4 exome AF: 0.0496 AC: 71810 AN: 1447900 Hom.: 2062 Cov.: 29 AF XY: 0.0489 AC XY: 35170 AN XY: 719514

Gnomad4 AFR exome AF: 0.00895

Gnomad4 AMR exome AF: 0.0389

Gnomad4 ASJ exome AF: 0.0477

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.0180

Gnomad4 FIN exome AF: 0.0156

Gnomad4 NFE exome AF: 0.0571

Gnomad4 OTH exome AF: 0.0471

GnomAD4 genome AF: 0.0360 AC: 5479 AN: 152282 Hom.: 158 Cov.: 32 AF XY: 0.0348 AC XY: 2592 AN XY: 74456

Gnomad4 AFR AF: 0.00994

Gnomad4 AMR AF: 0.0548

Gnomad4 ASJ AF: 0.0467

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0160

Gnomad4 FIN AF: 0.0129

Gnomad4 NFE AF: 0.0541

Gnomad4 OTH AF: 0.0483

Alfa AF: 0.0517 Hom.: 350

Bravo AF: 0.0384

TwinsUK AF: 0.0580 AC: 215

ALSPAC AF: 0.0563 AC: 217

ESP6500AA AF: 0.0114 AC: 41

ESP6500EA AF: 0.0552 AC: 451

ExAC AF: 0.0362 AC: 4366

Asia WGS AF: 0.00983 AC: 34 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Asn1678Ser in exon 43 of OTOGL: This variant is not expected to have clinical si gnificance because it has been identified in 5.5% (451/8174) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs61735664). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;.;D
MetaRNN	Benign	0.0051	T;T;T
MetaSVM	Benign	-0.58	T
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.2	.;.;D
REVEL	Benign	0.24
Sift	Uncertain	0.012	.;.;D
Sift4G	Uncertain	0.015	.;.;D
Vest4		0.51
MPC		0.17
ClinPred		0.0041	T
GERP RS		5.0
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs61735664; hg19: chr12-80735737; COSMIC: COSV54020765; COSMIC: COSV54020765;