rs370298976

chr12-80232988-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001378609.3(OTOGL):c.708C>T(p.Asp236=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000949 in 1,598,528 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (17 hom.)
• Consequence: OTOGL NM_001378609.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.98

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 12-80232988-C-T is Benign according to our data. Variant chr12-80232988-C-T is described in ClinVar as [Benign]. Clinvar id is 226974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.98 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00065 (99/152272) while in subpopulation SAS AF= 0.00975 (47/4822). AF 95% confidence interval is 0.00753. There are 0 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.708C>T	p.Asp236=	synonymous_variant	9/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.708C>T	p.Asp236=	synonymous_variant	9/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.708C>T	p.Asp236=	synonymous_variant	14/63
OTOGL	ENST00000643417.1	n.1368C>T		non_coding_transcript_exon_variant	12/23

Frequencies

GnomAD3 genomes AF: 0.000651 AC: 99 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00974

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00171 AC: 401 AN: 234356 Hom.: 7 AF XY: 0.00228 AC XY: 292 AN XY: 128080

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000669

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000565

Gnomad SAS exome AF: 0.0103

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000422

Gnomad OTH exome AF: 0.00272

GnomAD4 exome AF: 0.000980 AC: 1418 AN: 1446256 Hom.: 17 Cov.: 31 AF XY: 0.00129 AC XY: 931 AN XY: 719874

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0100

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000398

Gnomad4 OTH exome AF: 0.000714

GnomAD4 genome AF: 0.000650 AC: 99 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 49 AN XY: 74464

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00975

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000618

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000726 Hom.: 0

Bravo AF: 0.000423

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.00101

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 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. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	OTOGL: BP4, BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 05, 2016

p.Asp227Asp in exon 8 of OTOGL: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 1% (160/16356) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	13
Dann	Benign	0.52

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: rs370298976; hg19: chr12-80626768; COSMIC: COSV72007195;