rs563003848

chr11-17635152-G-Achr11-17635152-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001292063.2(OTOG):c.7658G>A(p.Arg2553His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000678 in 1,547,862 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2553P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000069 (1 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.63

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15241158).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.7658G>A	p.Arg2553His	missense_variant	46/56	ENST00000399397.6
OTOG	NM_001277269.2	c.7694G>A	p.Arg2565His	missense_variant	45/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.7658G>A	p.Arg2553His	missense_variant	46/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.7694G>A	p.Arg2565His	missense_variant	45/55	5		A2
OTOG	ENST00000342528.2	n.4606-458G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 151906 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000567 AC: 8 AN: 141106 Hom.: 0 AF XY: 0.0000523 AC XY: 4 AN XY: 76466

Gnomad AFR exome AF: 0.000156

Gnomad AMR exome AF: 0.0000410

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000893

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000805

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000688 AC: 96 AN: 1395956 Hom.: 1 Cov.: 33 AF XY: 0.0000726 AC XY: 50 AN XY: 688542

Gnomad4 AFR exome AF: 0.000348

Gnomad4 AMR exome AF: 0.0000561

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.000152

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000630

Gnomad4 OTH exome AF: 0.0000345

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 151906 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74154

Gnomad4 AFR AF: 0.000218

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000407 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000463 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-0.057
Eigen_PC	Benign	-0.048
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Benign	0.085
Sift	Uncertain	0.0070	D;.
Sift4G	Benign	0.085	T;T
Vest4		0.11
MutPred		0.57		Loss of disorder (P = 0.083);.;
MVP		0.18
ClinPred		0.12	T
GERP RS		3.5
Varity_R		0.11
gMVP		0.72

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: rs563003848; hg19: chr11-17656699; COSMIC: COSV100695993;