2-63055927-G-A

Position:

chr2-63055927-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_014562.4(OTX1):c.676G>A(p.Gly226Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,612,628 control chromosomes in the GnomAD database, including 25 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 0.0074 ( 12 hom., cov: 32)

Exomes 𝑓: 0.00081 ( 13 hom. )

Consequence

OTX1
NM_014562.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.715

Variant links:

Genes affected

OTX1 (HGNC:8521): (orthodenticle homeobox 1) This gene encodes a member of the bicoid sub-family of homeodomain-containing transcription factors. The encoded protein acts as a transcription factor and may play a role in brain and sensory organ development. A similar protein in mouse is required for proper brain and sensory organ development and can cause epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

OTX1 links:

OTX1 (HGNC:):

OTX1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006682873).

BP6

Variant 2-63055927-G-A is Benign according to our data. Variant chr2-63055927-G-A is described in ClinVar as [Benign]. Clinvar id is 710892.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00745 (1134/152256) while in subpopulation AFR AF= 0.0255 (1058/41538). AF 95% confidence interval is 0.0242. There are 12 homozygotes in gnomad4. There are 516 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1134 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTX1	NM_014562.4 linkuse as main transcript	c.676G>A	p.Gly226Ser	missense_variant	5/5	ENST00000282549.7	NP_055377.1	P32242
OTX1	NM_001199770.2 linkuse as main transcript	c.676G>A	p.Gly226Ser	missense_variant	5/5		NP_001186699.1	P32242
OTX1	NR_130153.2 linkuse as main transcript	n.1039G>A		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
OTX1	ENST00000282549.7 linkuse as main transcript	c.676G>A	p.Gly226Ser	missense_variant	5/5	1	NM_014562.4	ENSP00000282549.2	P32242
OTX1	ENST00000366671.7 linkuse as main transcript	c.676G>A	p.Gly226Ser	missense_variant	5/5	3		ENSP00000355631.3	P32242
OTX1	ENST00000405984.8 linkuse as main transcript	n.*485G>A		non_coding_transcript_exon_variant	5/5	2		ENSP00000385782.4	B5MC54
OTX1	ENST00000405984.8 linkuse as main transcript	n.*485G>A		3_prime_UTR_variant	5/5	2		ENSP00000385782.4	B5MC54

Frequencies

GnomAD3 genomes

AF:

0.00741

AC:

1128

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0254

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00367

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:

0.0000882

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00204

AC:

507

AN:

248344

Hom.:

AF XY:

0.00135

AC XY:

181

AN XY:

134500

show subpopulations

Gnomad AFR exome

AF:

0.0272

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.0000998

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000107

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000811

AC:

1185

AN:

1460372

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

478

AN XY:

726592

show subpopulations

Gnomad4 AFR exome

AF:

0.0261

Gnomad4 AMR exome

AF:

0.00190

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000576

Gnomad4 OTH exome

AF:

0.00225

GnomAD4 genome

AF:

0.00745

AC:

1134

AN:

152256

Hom.:

Cov.:

AF XY:

0.00693

AC XY:

516

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0255

Gnomad4 AMR

AF:

0.00366

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00663

Alfa

AF:

0.00292

Hom.:

Bravo

AF:

0.00862

ESP6500AA

AF:

0.0304

AC:

134

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00246

AC:

299

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

OTX1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.37

T;T

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.49

LIST_S2

Uncertain

0.90

.;D

MetaRNN

Benign

0.0067

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.87

N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.57

N;N

REVEL

Benign

0.13

Sift

Benign

0.75

T;T

Sift4G

Benign

0.92

T;T

Polyphen

0.039

B;B

Vest4

0.097

MVP

0.74

ClinPred

0.0029

GERP RS

1.8

Varity_R

0.043

gMVP

0.59

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