rs1851833422

Variant names:

• chr11-17547483-C-A
• rs1851833422
• NM_001292063.2:c.94+17C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-17547483-C-A
• chr11-17547483-C-G
• chr11-17547483-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001277269.2(OTOG):​c.111C>A​(p.Asp37Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000168 in 1,192,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D37D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: OTOG NM_001277269.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.483

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062347084).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.94+17C>A		intron_variant	Intron 1 of 55	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.111C>A	p.Asp37Glu	missense_variant	Exon 1 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.94+17C>A		intron_variant	Intron 1 of 55	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.111C>A	p.Asp37Glu	missense_variant	Exon 1 of 55	5		ENSP00000382323.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000168 AC: 2 AN: 1192260 Hom.: 0 Cov.: 31 AF XY: 0.00000348 AC XY: 2 AN XY: 575048

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24180

American (AMR) AF: 0.0000740 AC: 1 AN: 13512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16662

East Asian (EAS) AF: 0.00 AC: 0 AN: 27968

South Asian (SAS) AF: 0.00 AC: 0 AN: 47958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4888

European-Non Finnish (NFE) AF: 0.00000102 AC: 1 AN: 981816

Other (OTH) AF: 0.00 AC: 0 AN: 48870

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N
PhyloP100		0.48
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.12
Sift	Benign	0.57	T
Sift4G	Benign	1.0	T
Vest4		0.051
MutPred		0.15		Gain of methylation at R40 (P = 0.0794);
MVP		0.061
ClinPred		0.14	T
GERP RS		4.2
PromoterAI		0.037	Neutral
Varity_R		0.092
gMVP		0.025
Mutation Taster		=96/4	polymorphism

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

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Other links and lift over

dbSNP: rs1851833422; hg19: chr11-17569030;