rs144060182

chr11-17578490-G-Achr11-17578490-G-T

Variant summary

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

The NM_001292063.2(OTOG):c.2723G>A(p.Arg908His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,539,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. R908L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92

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=0.06922752).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.2723G>A	p.Arg908His	missense_variant	23/56	ENST00000399397.6
OTOG	NM_001277269.2	c.2759G>A	p.Arg920His	missense_variant	22/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.2723G>A	p.Arg908His	missense_variant	23/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.2759G>A	p.Arg920His	missense_variant	22/55	5		A2
OTOG	ENST00000342528.2	n.227G>A		non_coding_transcript_exon_variant	1/22	2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000144 AC: 2 AN: 139106 Hom.: 0 AF XY: 0.0000264 AC XY: 2 AN XY: 75642

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000187

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000793 AC: 11 AN: 1387136 Hom.: 0 Cov.: 32 AF XY: 0.0000131 AC XY: 9 AN XY: 684564

Gnomad4 AFR exome AF: 0.0000633

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000649

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000459 AC: 7 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74506

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.0000653

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

Bravo AF: 0.0000453

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	12
Dann	Uncertain	0.99
DEOGEN2	Benign	0.022	T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.069	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.47	N;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.5	N;.
REVEL	Benign	0.047
Sift	Benign	0.29	T;.
Sift4G	Benign	1.0	T;T
Vest4		0.088
MVP		0.13
ClinPred		0.097	T
GERP RS		1.4
Varity_R		0.030
gMVP		0.21

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: rs144060182; hg19: chr11-17600037;