rs532385451

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_001292063.2(OTOG):c.7380T>A(p.Asp2460Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,550,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.800

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=0.0055246353).

BP6

Variant 11-17634181-T-A is Benign according to our data. Variant chr11-17634181-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229103.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000171 (239/1398076) while in subpopulation AMR AF= 0.00199 (71/35704). AF 95% confidence interval is 0.00162. There are 0 homozygotes in gnomad4_exome. There are 107 alleles in male gnomad4_exome 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.7380T>A	p.Asp2460Glu	missense_variant	Exon 44 of 56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.7416T>A	p.Asp2472Glu	missense_variant	Exon 43 of 55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOG	ENST00000399397.6 link	c.7380T>A	p.Asp2460Glu	missense_variant	Exon 44 of 56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 link	c.7416T>A	p.Asp2472Glu	missense_variant	Exon 43 of 55	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000342528.2 link	n.4605+307T>A		intron_variant	Intron 19 of 21	2

Frequencies

GnomAD3 genomes

AF:

0.000270

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

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:

0.000265

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000443

AC:

AN:

146832

Hom.:

AF XY:

0.000316

AC XY:

AN XY:

79204

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00216

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:

0.000203

Gnomad OTH exome

AF:

0.000234

GnomAD4 exome

AF:

0.000171

AC:

239

AN:

1398076

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

107

AN XY:

689568

show subpopulations

Gnomad4 AFR exome

AF:

0.0000317

Gnomad4 AMR exome

AF:

0.00199

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000146

Gnomad4 OTH exome

AF:

0.000155

GnomAD4 genome

AF:

0.000269

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000223

Hom.:

Bravo

AF:

0.000325

ExAC

AF:

0.0000963

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 18B

Uncertain:1

May 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Aug 24, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asp2472Glu variant in OTOG is classified as likely benign because it has b een identified in 0.2% (54/24684) of Latino chromosomes by the Genome Aggregatio n Database (gnomAD, http://gnomad.broadinstitute.org, dbSNP rs532385451) and the aspartic acid residue (Asp) at position 2472 is not conserved in mammals and ev olutionary distant species, raising the possibility that a change at this positi on may be tolerated. Computational prediction tools and conservation analysis su ggest that the p.Asp2472Glu variant may not impact the protein. In addition, thi s variant has previously been detected by our laboratory in an individual with h earing loss who was compound heterozygous for one likely pathogenic and one path ogenic GJB2 variants. ACMG/AMP Criteria applied: BS1_Supporting, BP4, PM5. -

not provided

Benign:1

Nov 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.70

CADD

Benign

6.9

DANN

Benign

0.74

DEOGEN2

Benign

0.012

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.67

T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.0055

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.57

N;.

PrimateAI

Benign

0.43

PROVEAN

Benign

1.1

N;.

REVEL

Benign

0.012

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;T

Vest4

0.046

MutPred

0.42

Gain of glycosylation at P2476 (P = 0.117);.;

MVP

0.030

ClinPred

0.037

GERP RS

-0.85

Varity_R

0.021

gMVP

0.36

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

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