rs118083195

Positions:

• chr11-17557241-G-A
• chr11-17557241-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001292063.2(OTOG):​c.783G>A​(p.Met261Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,398,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.11

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]

OTOG (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32779104).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.783G>A	p.Met261Ile	missense_variant	8/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.819G>A	p.Met273Ile	missense_variant	7/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.783G>A	p.Met261Ile	missense_variant	8/56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.819G>A	p.Met273Ile	missense_variant	7/55	5		ENSP00000382323.2
OTOG	ENST00000485669.1	n.322G>A		non_coding_transcript_exon_variant	2/3	4
OTOG	ENST00000498332.5	n.689G>A		non_coding_transcript_exon_variant	7/16	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000670 AC: 1 AN: 149276 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 80384

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398334 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 689688

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: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.061	T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.98	L;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.7	N;.
REVEL	Benign	0.23
Sift	Uncertain	0.021	D;.
Sift4G	Uncertain	0.010	D;D
Vest4		0.56
MutPred		0.54		Loss of catalytic residue at M273 (P = 0.047);.;
MVP		0.43
ClinPred		0.88	D
GERP RS		5.8
Varity_R		0.32
gMVP		0.69

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: rs118083195; hg19: chr11-17578788;