rs76297160

chr12-80251766-A-G

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.1126A>G(p.Ile376Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,588,680 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (30 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (32 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.49

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=0.004940301).
• BP6: Variant 12-80251766-A-G is Benign according to our data. Variant chr12-80251766-A-G is described in ClinVar as [Benign]. Clinvar id is 226926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0104 (1589/152230) while in subpopulation AFR AF= 0.036 (1496/41528). AF 95% confidence interval is 0.0345. There are 30 homozygotes in gnomad4. There are 748 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.1126A>G	p.Ile376Val	missense_variant	12/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.1126A>G	p.Ile376Val	missense_variant	12/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.1126A>G	p.Ile376Val	missense_variant	17/63
OTOGL	ENST00000643417.1	n.1786A>G		non_coding_transcript_exon_variant	15/23

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1584 AN: 152112 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0360

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00272 AC: 562 AN: 206564 Hom.: 13 AF XY: 0.00218 AC XY: 240 AN XY: 110282

Gnomad AFR exome AF: 0.0389

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00109 AC: 1562 AN: 1436450 Hom.: 32 Cov.: 30 AF XY: 0.000974 AC XY: 693 AN XY: 711600

Gnomad4 AFR exome AF: 0.0393

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000366

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000300

Gnomad4 OTH exome AF: 0.00227

GnomAD4 genome AF: 0.0104 AC: 1589 AN: 152230 Hom.: 30 Cov.: 32 AF XY: 0.0100 AC XY: 748 AN XY: 74436

Gnomad4 AFR AF: 0.0360

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00172 Hom.: 5

Bravo AF: 0.0119

ESP6500AA AF: 0.0356 AC: 135

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00283 AC: 341

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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	Ile367Val in exon 11 of OTOGL: This variant is not expected to have clinical sig nificance because it has been identified in 3.6% (135/3794) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs76297160). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	16
Dann	Benign	0.95
Eigen	Benign	-0.018
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.75	T;.;T
MetaRNN	Benign	0.0049	T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	0.67	N;N
PrimateAI	Benign	0.39	T
Vest4		0.15
MVP		0.34
MPC		0.021
ClinPred		0.013	T
GERP RS		4.3
gMVP		0.25

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: rs76297160; hg19: chr12-80645546;