rs1554970485

Positions:

• chr11-17574813-T-C
• chr11-17574813-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001292063.2(OTOG):​c.2387T>C​(p.Val796Ala) 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 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: -0.0300

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03121829).
• BP6: Variant 11-17574813-T-C is Benign according to our data. Variant chr11-17574813-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 504963.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.2387T>C	p.Val796Ala	missense_variant	20/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.2423T>C	p.Val808Ala	missense_variant	19/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.2387T>C	p.Val796Ala	missense_variant	20/56	5	NM_001292063.2	ENSP00000382329	P2
OTOG	ENST00000399391.7	c.2423T>C	p.Val808Ala	missense_variant	19/55	5		ENSP00000382323	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

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

May 05, 2016

p.Val808Ala in exon 19 of OTOG: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, twelve mammals have an alanine (Ala) at this position despite high nearby a mino acid conservation. In addition, computational tools do not suggest a high l ikelihood of impact to the protein. Data from large population studies are insuf ficient to assess the frequency of this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.2
DANN	Benign	0.53
DEOGEN2	Benign	0.052	T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.43	T;T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.031	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.23	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.25	N;.
REVEL	Benign	0.019
Sift	Benign	0.71	T;.
Sift4G	Benign	1.0	T;T
Vest4		0.031
MutPred		0.32		Loss of stability (P = 0.1424);.;
MVP		0.030
ClinPred		0.021	T
GERP RS		-1.7
Varity_R		0.031
gMVP		0.48

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: rs1554970485; hg19: chr11-17596360;