12-80262052-A-T

Position:

• chr12-80262052-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.1973A>T​(p.His658Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00236 in 1,612,944 control chromosomes in the GnomAD database, including 128 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (112 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.79

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]

OTOGL (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025278926).
• BP6: Variant 12-80262052-A-T is Benign according to our data. Variant chr12-80262052-A-T is described in ClinVar as [Benign]. Clinvar id is 226929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0677 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.1973A>T	p.His658Leu	missense_variant	19/59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.1973A>T	p.His658Leu	missense_variant	19/59	5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1	c.1973A>T	p.His658Leu	missense_variant	24/63			ENSP00000496036.1
OTOGL	ENST00000643417.1	n.2633A>T		non_coding_transcript_exon_variant	22/23

Frequencies

GnomAD3 genomes AF: 0.00313 AC: 477 AN: 152172 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0740

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00640 AC: 1577 AN: 246388 Hom.: 54 AF XY: 0.00597 AC XY: 799 AN XY: 133890

Gnomad AFR exome AF: 0.000582

Gnomad AMR exome AF: 0.00582

Gnomad ASJ exome AF: 0.00239

Gnomad EAS exome AF: 0.0710

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000815

Gnomad OTH exome AF: 0.00398

GnomAD4 exome AF: 0.00228 AC: 3335 AN: 1460654 Hom.: 112 Cov.: 31 AF XY: 0.00224 AC XY: 1630 AN XY: 726598

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00507

Gnomad4 ASJ exome AF: 0.00245

Gnomad4 EAS exome AF: 0.0635

Gnomad4 SAS exome AF: 0.00152

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000810

Gnomad4 OTH exome AF: 0.00486

GnomAD4 genome AF: 0.00312 AC: 475 AN: 152290 Hom.: 16 Cov.: 32 AF XY: 0.00325 AC XY: 242 AN XY: 74462

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.0738

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00229 Hom.: 8

Bravo AF: 0.00360

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00132 AC: 5

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00608 AC: 735

Asia WGS AF: 0.0310 AC: 107 AN: 3478

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	His649Leu in exon 18 of OTOGL: This variant is not expected to have clinical sig nificance because it has been identified in 6.5% (13/200) of Han Chinese chromos omes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.ni h.gov/projects/SNP; dbSNP rs79711087). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 17, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Benign	0.97
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T;.;T
MetaRNN	Benign	0.0025	T;T;T
MetaSVM	Benign	-0.94	T
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-4.4	.;.;D
REVEL	Benign	0.16
Sift	Benign	0.56	.;.;T
Sift4G	Benign	0.27	.;.;T
Vest4		0.47
MVP		0.29
MPC		0.057
ClinPred		0.034	T
GERP RS		4.2
gMVP		0.46

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: rs79711087; hg19: chr12-80655832;