rs876657948

Positions:

• chr12-80313630-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001378609.3(OTOGL):​c.3605G>A​(p.Cys1202Tyr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,456,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: OTOGL NM_001378609.3 missense, splice_region
• Scores: Splicing: ADA: 0.9659
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.50

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.3605G>A	p.Cys1202Tyr	missense_variant, splice_region_variant	31/59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.3605G>A	p.Cys1202Tyr	missense_variant, splice_region_variant	31/59	5	NM_001378609.3	ENSP00000447211	P1
OTOGL	ENST00000646859.1	c.3470G>A	p.Cys1157Tyr	missense_variant, splice_region_variant	35/63			ENSP00000496036

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1456638 Hom.: 0 Cov.: 31 AF XY: 0.00000828 AC XY: 6 AN XY: 724706

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000831

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 16, 2015

The p.Cys1193Tyr variant in OTOGL has not been previously reported in individual s with hearing loss or in large population studies. Computational prediction too ls and conservation analysis do not provide strong support for or against an imp act to the protein. This variant is located in the last three bases of the exon, which is part of the 5? splice region. While computational tools do not suggest an impact to splicing, this information is not predictive enough to rule out pa thogenicity. In summary, the clinical significance of the p.Cys1193Tyr variant i s uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.76	T;.;T
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-9.1	.;.;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	.;.;D
Sift4G	Pathogenic	0.0	.;.;D
Vest4		0.99
MutPred		0.99		.;.;Loss of glycosylation at S1190 (P = 0.3127);
MVP		0.71
MPC		0.22
ClinPred		1.0	D
GERP RS		5.8
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.82
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: rs876657948; hg19: chr12-80707410;