rs181528168

chr12-80229286-G-A

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.519G>A(p.Ser173=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,597,354 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (5 hom.)
• Consequence: OTOGL NM_001378609.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.208

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=-0.41).
• BP6: Variant 12-80229286-G-A is Benign according to our data. Variant chr12-80229286-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 504790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.208 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00177 (2554/1445264) while in subpopulation SAS AF= 0.00361 (311/86202). AF 95% confidence interval is 0.00328. There are 5 homozygotes in gnomad4_exome. There are 1324 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.519G>A	p.Ser173=	synonymous_variant	8/59	ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.519G>A	p.Ser173=	synonymous_variant	8/59	5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.519G>A	p.Ser173=	synonymous_variant	13/63
OTOGL	ENST00000643417.1	n.1179G>A		non_coding_transcript_exon_variant	11/23

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 151972 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.00302

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00175

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00143 AC: 335 AN: 234266 Hom.: 3 AF XY: 0.00162 AC XY: 207 AN XY: 128034

Gnomad AFR exome AF: 0.000198

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00321

Gnomad FIN exome AF: 0.00266

Gnomad NFE exome AF: 0.00172

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.00177 AC: 2554 AN: 1445264 Hom.: 5 Cov.: 30 AF XY: 0.00184 AC XY: 1324 AN XY: 719484

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00361

Gnomad4 FIN exome AF: 0.00297

Gnomad4 NFE exome AF: 0.00181

Gnomad4 OTH exome AF: 0.00148

GnomAD4 genome AF: 0.00126 AC: 191 AN: 152090 Hom.: 0 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74338

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00271

Gnomad4 FIN AF: 0.00302

Gnomad4 NFE AF: 0.00175

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00133 Hom.: 0

Bravo AF: 0.000997

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00190

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Ser164Ser in exon 7 of OTOGL: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 0.3% (27/8174) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs181528168). -

OTOGL-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 14, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	6.1
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs181528168; hg19: chr12-80623066;