rs200115208

chr12-80328756-C-T

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.4279+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,574,412 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (20 hom.)
• Consequence: OTOGL NM_001378609.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.80

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 (BayesDel_noAF=-0.88).
• BP6: Variant 12-80328756-C-T is Benign according to our data. Variant chr12-80328756-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 226948.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 = 0.000821 (125/152250) while in subpopulation SAS AF= 0.0102 (49/4824). AF 95% confidence interval is 0.00789. There are 0 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOGL	NM_001378609.3	c.4279+12C>T		intron_variant		ENST00000547103.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOGL	ENST00000547103.7	c.4279+12C>T		intron_variant		5	NM_001378609.3	P1
OTOGL	ENST00000646859.1	c.4144+12C>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152132 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00994

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00188 AC: 453 AN: 240648 Hom.: 8 AF XY: 0.00241 AC XY: 315 AN XY: 130484

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000777

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000284

Gnomad SAS exome AF: 0.0119

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000590

Gnomad OTH exome AF: 0.00287

GnomAD4 exome AF: 0.00113 AC: 1602 AN: 1422162 Hom.: 20 Cov.: 31 AF XY: 0.00147 AC XY: 1041 AN XY: 708778

Gnomad4 AFR exome AF: 0.0000925

Gnomad4 AMR exome AF: 0.000934

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000127

Gnomad4 SAS exome AF: 0.0114

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000478

Gnomad4 OTH exome AF: 0.000863

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.000819 AC XY: 61 AN XY: 74460

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0102

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000753 Hom.: 0

Bravo AF: 0.000665

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 04, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 05, 2016

c.4252+12C>T in intron 35 of OTOGL: This variant is not expected to have clinica l significance because it is not located within the conserved splice consensus s equence. It has been identified in 1.2% (174/14558) of South Asian chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.17
Dann	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200115208; hg19: chr12-80722536;