rs548278514

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_001292063.2(OTOG):c.7510G>A(p.Ala2504Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,475,916 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.32

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]

OTOG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008938849).

BP6

Variant 11-17634873-G-A is Benign according to our data. Variant chr11-17634873-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227795.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00117 (173/147376) while in subpopulation AFR AF= 0.00394 (160/40580). AF 95% confidence interval is 0.00344. There are 0 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.7510G>A	p.Ala2504Thr	missense_variant	Exon 45 of 56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.7546G>A	p.Ala2516Thr	missense_variant	Exon 44 of 55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOG	ENST00000399397.6 link	c.7510G>A	p.Ala2504Thr	missense_variant	Exon 45 of 56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 link	c.7546G>A	p.Ala2516Thr	missense_variant	Exon 44 of 55	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000342528.2 link	n.4606-737G>A		intron_variant	Intron 19 of 21	2

Frequencies

GnomAD3 genomes

AF:

0.00117

AC:

173

AN:

147246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00395

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000404

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:

0.0000150

Gnomad OTH

AF:

0.00293

GnomAD3 exomes

AF:

0.000232

AC:

AN:

146336

Hom.:

AF XY:

0.000152

AC XY:

AN XY:

78958

show subpopulations

Gnomad AFR exome

AF:

0.00282

Gnomad AMR exome

AF:

0.000489

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000888

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000236

GnomAD4 exome

AF:

0.000126

AC:

168

AN:

1328540

Hom.:

Cov.:

AF XY:

0.0000993

AC XY:

AN XY:

654402

show subpopulations

Gnomad4 AFR exome

AF:

0.00336

Gnomad4 AMR exome

AF:

0.000538

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000255

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000348

Gnomad4 OTH exome

AF:

0.000244

GnomAD4 genome

AF:

0.00117

AC:

173

AN:

147376

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

71868

show subpopulations

Gnomad4 AFR

AF:

0.00394

Gnomad4 AMR

AF:

0.000403

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000150

Gnomad4 OTH

AF:

0.00290

Alfa

AF:

0.000820

Hom.:

Bravo

AF:

0.00127

ExAC

AF:

0.000100

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jan 18, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Feb 23, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala2516Thr in exon 44 of OTOG: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals, sug gesting that variants at this position are tolerated. Of note, 5 mammals (Bactri an camel, elephant shrew, oposum, Tasmanian devil, and wallaby) have a threonine (Thr) this position despite high nearby amino acid conservation. In addition, c omputational prediction tools do not suggest a high likelihood of impact to the protein. The variant has been reported in 2/802 African chromosomes by the Exome Aggregate Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs548278514) . -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.025

T;.

Eigen

Benign

-0.023

Eigen_PC

Benign

0.078

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.041

MetaRNN

Benign

0.0089

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.075

N;.

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.39

N;N

REVEL

Benign

0.037

Sift

Benign

0.32

T;T

Sift4G

Benign

0.49

T;T

Vest4

0.068

MVP

0.21

ClinPred

0.033

GERP RS

4.2

Varity_R

0.030

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over