11-17606135-G-T

Position:

• chr11-17606135-G-T

Variant summary

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

The NM_001292063.2(OTOG):​c.4156G>T​(p.Asp1386Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000218 in 1,374,806 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.4156G>T	p.Asp1386Tyr	missense_variant, splice_region_variant	33/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.4192G>T	p.Asp1398Tyr	missense_variant, splice_region_variant	32/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.4156G>T	p.Asp1386Tyr	missense_variant, splice_region_variant	33/56	5	NM_001292063.2	ENSP00000382329	P2
OTOG	ENST00000399391.7	c.4192G>T	p.Asp1398Tyr	missense_variant, splice_region_variant	32/55	5		ENSP00000382323	A2
OTOG	ENST00000342528.2	n.1494G>T		splice_region_variant, non_coding_transcript_exon_variant	9/22	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000218 AC: 3 AN: 1374806 Hom.: 0 Cov.: 35 AF XY: 0.00000148 AC XY: 1 AN XY: 674144

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: 0.00000188

Gnomad4 OTH exome AF: 0.0000176

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	35
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-4.2	D;.
REVEL	Benign	0.29
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.024	D;D
Vest4		0.54
MutPred		0.51		Loss of ubiquitination at K1400 (P = 0.0363);.;
MVP		0.54
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.33
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.40		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;