rs7312569

Positions:

• chr12-80353429-C-G
• chr12-80353429-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001378609.3(OTOGL):​c.5512C>G​(p.Leu1838Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,600,620 control chromosomes in the GnomAD database, including 30,377 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2751 hom., cov: 33)
  • Exomes 𝑓: 0.19 (27626 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.325

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 -16 ACMG points.

• BP6: Variant 12-80353429-C-G is Benign according to our data. Variant chr12-80353429-C-G is described in ClinVar as [Benign]. Clinvar id is 226956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-80353429-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.5512C>G	p.Leu1838Val	missense_variant	46/59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.5512C>G	p.Leu1838Val	missense_variant	46/59	5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1	c.5377C>G	p.Leu1793Val	missense_variant	50/63			ENSP00000496036.1
OTOGL	ENST00000298820.7	c.811C>G	p.Leu271Val	missense_variant	7/18	5		ENSP00000298820.3

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28086 AN: 152054 Hom.: 2750 Cov.: 33

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.0512

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.217

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.190

GnomAD3 exomes AF: 0.176 AC: 40545 AN: 229808 Hom.: 3888 AF XY: 0.179 AC XY: 22249 AN XY: 124084

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.200

Gnomad ASJ exome AF: 0.185

Gnomad EAS exome AF: 0.0441

Gnomad SAS exome AF: 0.212

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.195

Gnomad OTH exome AF: 0.189

GnomAD4 exome AF: 0.191 AC: 276908 AN: 1448448 Hom.: 27626 Cov.: 30 AF XY: 0.192 AC XY: 138055 AN XY: 719156

Gnomad4 AFR exome AF: 0.176

Gnomad4 AMR exome AF: 0.205

Gnomad4 ASJ exome AF: 0.187

Gnomad4 EAS exome AF: 0.0385

Gnomad4 SAS exome AF: 0.208

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.199

Gnomad4 OTH exome AF: 0.187

GnomAD4 genome AF: 0.185 AC: 28088 AN: 152172 Hom.: 2751 Cov.: 33 AF XY: 0.182 AC XY: 13508 AN XY: 74410

Gnomad4 AFR AF: 0.181

Gnomad4 AMR AF: 0.215

Gnomad4 ASJ AF: 0.184

Gnomad4 EAS AF: 0.0513

Gnomad4 SAS AF: 0.217

Gnomad4 FIN AF: 0.107

Gnomad4 NFE AF: 0.199

Gnomad4 OTH AF: 0.188

Alfa AF: 0.190 Hom.: 2133

Bravo AF: 0.192

TwinsUK AF: 0.193 AC: 714

ALSPAC AF: 0.199 AC: 767

ESP6500AA AF: 0.177 AC: 688

ESP6500EA AF: 0.195 AC: 1621

ExAC AF: 0.175 AC: 21080

Asia WGS AF: 0.142 AC: 491 AN: 3476

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	Leu1829Val in exon 45 of OTOGL: This variant is not expected to have clinical si gnificance because it has been identified in 19.5% (1621/8296) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs7312569). -
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. -

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	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.95
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.74	T;.;T
MetaRNN	Benign	0.0041	T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.4	.;.;N
REVEL	Benign	0.071
Sift	Benign	0.072	.;.;T
Sift4G	Benign	0.13	.;.;T
Vest4		0.15
MPC		0.024
ClinPred		0.0015	T
GERP RS		0.45
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.43		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs7312569; hg19: chr12-80747209; COSMIC: COSV54016903; COSMIC: COSV54016903;