rs749226050

Positions:

• chr12-80279087-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001378609.3(OTOGL):​c.2849T>C​(p.Ile950Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.74

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2750178).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.2849T>C	p.Ile950Thr	missense_variant	26/59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.2849T>C	p.Ile950Thr	missense_variant	26/59	5	NM_001378609.3	ENSP00000447211	P1
OTOGL	ENST00000646859.1	c.2849T>C	p.Ile950Thr	missense_variant	31/63			ENSP00000496036

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000856 AC: 2 AN: 233774 Hom.: 0 AF XY: 0.00000782 AC XY: 1 AN XY: 127854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000184

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000840 AC: 1

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

Apr 25, 2017

The p.Ile941Thr variant in OTOGL has not been previously reported in individuals with hearing loss, but has been identified in 2/108040 European chromosomes by the Genome Aggregation Consortium (gnomAD, http://gnomad.broadinstitute.org; dbS NP rs749226050). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational pr ediction tools and conservation analyses suggest that this variant may not impac t the protein, though this information is not predictive enough to rule out path ogenicity. In summary, the clinical significance of the p.Ile941Thr variant is u ncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Benign	0.96
Eigen	Benign	0.046
Eigen_PC	Benign	0.081
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.75	T;.;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.7	.;.;N
REVEL	Benign	0.17
Sift	Benign	0.23	.;.;T
Sift4G	Benign	0.12	.;.;T
Vest4		0.68
MutPred		0.57		.;.;Loss of stability (P = 0.0117);
MVP		0.33
MPC		0.032
ClinPred		0.14	T
GERP RS		5.6
gMVP		0.67

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: rs749226050; hg19: chr12-80672867;