rs876657556

chr11-17553506-G-Cchr11-17553506-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001292063.2(OTOG):c.527G>C(p.Ser176Thr) 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. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. S176S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.51

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13606107).
• BP6: Variant 11-17553506-G-C is Benign according to our data. Variant chr11-17553506-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 227787.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.527G>C	p.Ser176Thr	missense_variant	6/56	ENST00000399397.6
OTOG	NM_001277269.2	c.563G>C	p.Ser188Thr	missense_variant	5/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.527G>C	p.Ser176Thr	missense_variant	6/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.563G>C	p.Ser188Thr	missense_variant	5/55	5		A2
OTOG	ENST00000498332.5	n.433G>C		non_coding_transcript_exon_variant	5/16	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 12, 2015

p.Ser188Thr in exon 5 of OTOG: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, 18 mammals have a Threonine (Thr) at this position. In addition, computation al prediction tools do not suggest a high likelihood of impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	17
Dann	Benign	0.88
DEOGEN2	Benign	0.036	T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.78	N;.
MutationTaster	Benign	0.71	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.88	N;.
REVEL	Benign	0.051
Sift	Benign	0.26	T;.
Sift4G	Benign	0.20	T;T
Vest4		0.086
MutPred		0.64		Loss of disorder (P = 0.0607);.;
MVP		0.29
ClinPred		0.057	T
GERP RS		2.3
Varity_R		0.057
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs876657556; hg19: chr11-17575053;