11-17547503-G-A

Position:

chr11-17547503-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001277269.2(OTOG):c.131G>A(p.Arg44Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,326,700 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 49 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 26 hom. )

Consequence

OTOG
NM_001277269.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.185

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002431661).

BP6

Variant 11-17547503-G-A is Benign according to our data. Variant chr11-17547503-G-A is described in ClinVar as [Benign]. Clinvar id is 226863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0127 (1935/152194) while in subpopulation AFR AF= 0.0446 (1850/41514). AF 95% confidence interval is 0.0429. There are 49 homozygotes in gnomad4. There are 908 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 49 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.94+37G>A		intron_variant		ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.131G>A	p.Arg44Gln	missense_variant	1/55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6 link	c.94+37G>A		intron_variant		5	NM_001292063.2	ENSP00000382329.2		H9KVB3
OTOG	ENST00000399391.7 link	c.131G>A	p.Arg44Gln	missense_variant	1/55	5		ENSP00000382323.2		Q6ZRI0-1

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1930

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0446

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.0129

GnomAD3 exomes

AF:

0.00240

AC:

AN:

9586

Hom.:

AF XY:

0.00245

AC XY:

AN XY:

5314

show subpopulations

Gnomad AFR exome

AF:

0.0364

Gnomad AMR exome

AF:

0.00173

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00107

AC:

1258

AN:

1174506

Hom.:

Cov.:

AF XY:

0.000949

AC XY:

536

AN XY:

564914

show subpopulations

Gnomad4 AFR exome

AF:

0.0425

Gnomad4 AMR exome

AF:

0.00299

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000451

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000247

Gnomad4 OTH exome

AF:

0.00346

GnomAD4 genome

AF:

0.0127

AC:

1935

AN:

152194

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

908

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0446

Gnomad4 AMR

AF:

0.00327

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.00207

Hom.:

Bravo

AF:

0.0145

ExAC

AF:

0.000690

AC:

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Arg44Gln in exon 1 of OTOG: This variant is not expected to have clinical signif icance because it has been identified in 4.5% (8/176) of Yoruba (Nigerian) chrom osomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm. nih.gov/projects/SNP; dbSNP rs111425080). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.79

CADD

Benign

2.3

DANN

Benign

0.86

DEOGEN2

Benign

0.028

Eigen

Benign

-0.90

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.40

MetaRNN

Benign

0.0024

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.90

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.25

REVEL

Benign

0.0050

Sift

Benign

0.15

Sift4G

Uncertain

0.056

Vest4

0.055

MVP

0.048

ClinPred

0.0035

GERP RS

-1.8

Varity_R

0.020

gMVP

0.11

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