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rs897016393

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001292063.2(OTOG):c.2911G>A(p.Ala971Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000516 in 1,550,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.38
Variant links:
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]

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ACMG classification

Classification made for transcript

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=0.28194636).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
OTOGNM_001292063.2 linkuse as main transcriptc.2911G>A p.Ala971Thr missense_variant 25/56 ENST00000399397.6
OTOGNM_001277269.2 linkuse as main transcriptc.2947G>A p.Ala983Thr missense_variant 24/55

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
OTOGENST00000399397.6 linkuse as main transcriptc.2911G>A p.Ala971Thr missense_variant 25/565 NM_001292063.2 P2
OTOGENST00000399391.7 linkuse as main transcriptc.2947G>A p.Ala983Thr missense_variant 24/555 A2Q6ZRI0-1
OTOGENST00000342528.2 linkuse as main transcriptn.372-1700G>A intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152216
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.0000201
AC:
3
AN:
149426
Hom.:
0
AF XY:
0.0000124
AC XY:
1
AN XY:
80436
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000814
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:
0.00000501
AC:
7
AN:
1398352
Hom.:
0
Cov.:
32
AF XY:
0.00000290
AC XY:
2
AN XY:
689696
show subpopulations
Gnomad4 AFR exome
AF:
0.0000949
Gnomad4 AMR exome
AF:
0.0000560
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000126
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.27e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152216
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
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:
0.0000986
Hom.:
0
Bravo
AF:
0.0000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 07, 2017The p.Ala983Thr variant in OTOG has not been previously reported in individuals with hearing loss, but has been identified in 2/23850 of Latino chromosomes and 1/52108 European chromosomes by the Genome Aggregation Database (gnomAD, http:// gnomad.broadinstitute.org; dbSNP rs897016393). Although this variant has been se en in the general population, its frequency is not high enough to rule out a pat hogenic role. Computational prediction tools and conservation analysis do not pr ovide strong support for or against an impact to the protein. In summary, the cl inical significance of the p.Ala983Thr variant is uncertain. ACMG/AMP criteria a pplied: PM2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.090
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.27
Cadd
Pathogenic
27
Dann
Pathogenic
1.0
DEOGEN2
Benign
0.039
T;.
Eigen
Uncertain
0.36
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Benign
0.054
D
MetaRNN
Benign
0.28
T;T
MetaSVM
Benign
-0.73
T
MutationAssessor
Benign
0.96
L;.
MutationTaster
Benign
0.99
D;D;D
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-0.63
N;.
REVEL
Benign
0.11
Sift
Uncertain
0.0060
D;.
Sift4G
Uncertain
0.0050
D;D
Vest4
0.24
MVP
0.45
ClinPred
0.63
D
GERP RS
3.8
Varity_R
0.17
gMVP
0.25

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs897016393; hg19: chr11-17613040; API