rs1554979068

Positions:

• chr11-17634165-C-A
• chr11-17634165-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.7364C>A​(p.Thr2455Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.95

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=0.15392601).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.7364C>A	p.Thr2455Asn	missense_variant	44/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.7400C>A	p.Thr2467Asn	missense_variant	43/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.7364C>A	p.Thr2455Asn	missense_variant	44/56	5	NM_001292063.2	ENSP00000382329	P2
OTOG	ENST00000399391.7	c.7400C>A	p.Thr2467Asn	missense_variant	43/55	5		ENSP00000382323	A2
OTOG	ENST00000342528.2	n.4605+291C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Jul 05, 2017

The p.Thr2467Asn variant in OTOG has not been previously reported in individuals with hearing loss or in large population studies. Computational prediction tool s and conservation analyses suggest that this variant may not impact the protein , though this information is not predictive enough to rule out pathogenicity. I n summary, the clinical significance of the p.Thr2467Asn variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.051	T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M;.
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N;.
REVEL	Benign	0.070
Sift	Benign	0.12	T;.
Sift4G	Uncertain	0.0030	D;D
Vest4		0.18
MutPred		0.53		Loss of glycosylation at T2467 (P = 0.0242);.;
MVP		0.076
ClinPred		0.32	T
GERP RS		3.9
Varity_R		0.086
gMVP		0.77

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: rs1554979068; hg19: chr11-17655712;