rs876657939

Positions:

• chr11-17606135-G-A
• chr11-17606135-G-C
• chr11-17606135-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001292063.2(OTOG):​c.4156G>A​(p.Asp1386Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: OTOG NM_001292063.2 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.76

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.4156G>A	p.Asp1386Asn	missense_variant, splice_region_variant	33/56	ENST00000399397.6
OTOG	NM_001277269.2	c.4192G>A	p.Asp1398Asn	missense_variant, splice_region_variant	32/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.4156G>A	p.Asp1386Asn	missense_variant, splice_region_variant	33/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.4192G>A	p.Asp1398Asn	missense_variant, splice_region_variant	32/55	5		A2
OTOG	ENST00000342528.2	n.1494G>A		splice_region_variant, non_coding_transcript_exon_variant	9/22	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

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 22, 2015

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp1398As n variant in OTOG has not been previously reported in individuals with hearing l oss and data from large population studies is insufficient to assess the frequen cy of this variant. This variant is located in the last base of the exon, which is part of the 5? splice region. Computational tools suggest an impact to splici ng; however, this information is not predictive enough to determine pathogenicit y. In summary, while there is some suspicion for a pathogenic role, the clinica l significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.68
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.2	N;.
REVEL	Benign	0.11
Sift	Benign	0.080	T;.
Sift4G	Benign	0.31	T;T
Vest4		0.25
MutPred		0.45		Loss of ubiquitination at K1400 (P = 0.0431);.;
MVP		0.20
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.12
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.39		Position offset: -34

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs876657939; hg19: chr11-17627682;