rs201877625

Positions:

• chr12-80377120-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001378609.3(OTOGL):​c.6782-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,596,548 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00072 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (47 hom.)
• Consequence: OTOGL NM_001378609.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001288
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0240

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 12-80377120-C-T is Benign according to our data. Variant chr12-80377120-C-T is described in ClinVar as [Benign]. Clinvar id is 226973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000724 (110/151956) while in subpopulation SAS AF= 0.0176 (85/4822). AF 95% confidence interval is 0.0146. There are 1 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 47 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.6782-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.6782-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001378609.3	P1

Frequencies

GnomAD3 genomes AF: 0.000731 AC: 111 AN: 151838 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00293 AC: 714 AN: 243594 Hom.: 12 AF XY: 0.00400 AC XY: 528 AN XY: 131864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000900

Gnomad ASJ exome AF: 0.000707

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0228

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000219

Gnomad OTH exome AF: 0.00202

GnomAD4 exome AF: 0.00140 AC: 2027 AN: 1444592 Hom.: 47 Cov.: 29 AF XY: 0.00206 AC XY: 1480 AN XY: 718554

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000688

Gnomad4 ASJ exome AF: 0.00120

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.0213

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000112

Gnomad4 OTH exome AF: 0.00138

GnomAD4 genome AF: 0.000724 AC: 110 AN: 151956 Hom.: 1 Cov.: 33 AF XY: 0.00113 AC XY: 84 AN XY: 74232

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0176

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.000336 Hom.: 1

Bravo AF: 0.000234

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 13, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 01, 2015

c.6755-3C>T in intron 56 of OTOGL: This variant is not expected to have clinical significance because it has been identified in 2.3% (357/15826) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs201877625). -

OTOGL-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 15, 2019

This variant is classified as 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	-0.40
CADD	Benign	8.4
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.11
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: rs201877625; hg19: chr12-80770900;