11-17547386-C-T

Position:

• chr11-17547386-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001292063.2(OTOG):​c.14C>T​(p.Ala5Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,260,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.319

Genes affected

OTOG (HGNC:8516): (otogelin) The protein encoded by this gene is a component of the acellular membranes of the inner ear. Disruption of the orthologous mouse gene shows that it plays a role in auditory and vestibular functions. It is involved in fibrillar network organization, the anchoring of otoconial membranes and cupulae to the neuroepithelia, and likely in sound stimulation resistance. Mutations in this gene cause autosomal recessive nonsyndromic deafness, type 18B. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.084825754).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.14C>T	p.Ala5Val	missense_variant	1/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.14C>T	p.Ala5Val	missense_variant	1/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.14C>T	p.Ala5Val	missense_variant	1/56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.14C>T	p.Ala5Val	missense_variant	1/55	5		ENSP00000382323.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000111 AC: 14 AN: 1260426 Hom.: 0 Cov.: 31 AF XY: 0.00000810 AC XY: 5 AN XY: 617222

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000127

Gnomad4 OTH exome AF: 0.0000193

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

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 07, 2016

The p.Ala5Val variant in OTOG has not been previously reported in individuals wi th hearing loss, and data from large population studies are insufficient to asse ss the frequency of this variant. Computational prediction tools and conservati on analyses suggest that this variant may not impact the protein, though this in formation is not predictive enough to rule out pathogenicity. In summary, the c linical significance of the p.Ala5Val variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.026	T;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.44	T;T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.085	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.47	N;N
REVEL	Benign	0.013
Sift	Uncertain	0.027	D;T
Sift4G	Uncertain	0.016	D;T
Vest4		0.15
MutPred		0.25		Loss of disorder (P = 0.0766);Loss of disorder (P = 0.0766);
MVP		0.030
ClinPred		0.040	T
GERP RS		0.085
Varity_R		0.032
gMVP		0.19

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: rs1018902503; hg19: chr11-17568933;