rs139375212

Positions:

chr12-80318586-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001378609.3(OTOGL):c.3675G>C(p.Gln1225His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,432,178 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 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 0.00079 ( 2 hom., cov: 33)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

OTOGL
NM_001378609.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.0580

Variant links:

Genes affected

OTOGL (HGNC:26901): (otogelin like) The protein encoded by this gene belongs to the otogelin family. This gene is expressed in the inner ear of vertebrates with the highest level of expression seen at the embryonic stage and lowest in adult. Knockdown studies in zebrafish suggest that this gene is essential for normal inner ear function. Mutations in this gene are associated with autosomal recessive deafness. [provided by RefSeq, Dec 2012]

OTOGL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0123848915).

BP6

Variant 12-80318586-G-C is Benign according to our data. Variant chr12-80318586-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227822.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOGL	NM_001378609.3 linkuse as main transcript	c.3675G>C	p.Gln1225His	missense_variant	33/59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7 linkuse as main transcript	c.3675G>C	p.Gln1225His	missense_variant	33/59	5	NM_001378609.3	ENSP00000447211	P1
OTOGL	ENST00000646859.1 linkuse as main transcript	c.3540G>C	p.Gln1180His	missense_variant	37/63			ENSP00000496036

Frequencies

GnomAD3 genomes

AF:

0.000743

AC:

113

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00205

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

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:

0.0000749

AC:

AN:

80156

Hom.:

AF XY:

0.0000460

AC XY:

AN XY:

43444

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.000272

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:

0.0000422

AC:

AN:

1279902

Hom.:

Cov.:

AF XY:

0.0000430

AC XY:

AN XY:

628190

show subpopulations

Gnomad4 AFR exome

AF:

0.00143

Gnomad4 AMR exome

AF:

0.000340

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000176

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000191

GnomAD4 genome

AF:

0.000788

AC:

120

AN:

152276

Hom.:

Cov.:

AF XY:

0.000779

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00221

Gnomad4 AMR

AF:

0.00183

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:

0.000206

Hom.:

Bravo

AF:

0.000820

ESP6500AA

AF:

0.00119

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000854

AC:

Asia WGS

AF:

0.000867

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2023	Reported as heterozygous in a patient with neonatal onset encephalopathy, brain atrophy with cerebellar malformation, and later-onset seizures who was also heterozygous for the p.(Q596H) variant; however, this patient harbored a homozygous nonsense variant in the TBCK gene which the authors concluded was likely the causative variant (Chong et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27040692) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The OTOGL p.Gln1216His variant was identified in dbSNP (ID: rs139375212) and ClinVar (classified as likely benign by Laboratory for Molecular Medicine) but was not identified in LOVD 3.0. The variant was identified in the literature in a family with TBCK-associated infantile syndromic encephalopathy; the OTOGL variant was not expected to contribute to the phenotype (Chong_2016_PMID:27040692). The variant was identified in control databases in 26 of 111558 chromosomes at a frequency of 0.0002331 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 24 of 12508 chromosomes (freq: 0.001919) and Latino in 2 of 8186 chromosomes (freq: 0.000244), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Other, or South Asian populations. The p.Gln1216 residue is conserved in mammals but not in more distantly related organisms however three out of four computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 22, 2022	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1216 of the OTOGL protein (p.Gln1216His). This variant is present in population databases (rs139375212, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with OTOGL-related conditions. ClinVar contains an entry for this variant (Variation ID: 227822). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

p.Gln1216His in exon 32 of OTOGL: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, five mammals (pig, hedgehog, elephant, elephant shrew, and platypus) have a histidine (His) at this position despite high nearby amino acid conservation. In addition, it has been identified in 4/2052 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs139375212) . -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.74

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.37

T;.;T

M_CAP

Benign

0.0032

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.82

.;.;N

REVEL

Benign

0.032

Sift

Benign

0.21

.;.;T

Sift4G

Uncertain

0.040

.;.;D

Vest4

0.071

MutPred

0.48

.;.;Gain of catalytic residue at S1217 (P = 0.1899);

MVP

0.081

MPC

0.022

ClinPred

0.0077

GERP RS

1.2

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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