Variant chr2-63055642-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014562.4(OTX1):c.391G>C(p.Ala131Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

OTX1
NM_014562.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.03

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22073019).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTX1	NM_014562.4 linkuse as main transcript	c.391G>C	p.Ala131Pro	missense_variant	5/5	ENST00000282549.7	NP_055377.1	P32242
OTX1	NM_001199770.2 linkuse as main transcript	c.391G>C	p.Ala131Pro	missense_variant	5/5		NP_001186699.1	P32242
OTX1	NR_130153.2 linkuse as main transcript	n.754G>C		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.391G>C	p.Ala131Pro	missense_variant	5/5	1	NM_014562.4	ENSP00000282549.2	P32242
OTX1	ENST00000366671.7 linkuse as main transcript	c.391G>C	p.Ala131Pro	missense_variant	5/5	3		ENSP00000355631.3	P32242
OTX1	ENST00000405984.8 linkuse as main transcript	n.*200G>C		non_coding_transcript_exon_variant	5/5	2		ENSP00000385782.4	B5MC54
OTX1	ENST00000405984.8 linkuse as main transcript	n.*200G>C		3_prime_UTR_variant	5/5	2		ENSP00000385782.4	B5MC54

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249334

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

135002

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461794

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2024

The c.391G>C (p.A131P) alteration is located in exon 5 (coding exon 3) of the OTX1 gene. This alteration results from a G to C substitution at nucleotide position 391, causing the alanine (A) at amino acid position 131 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.28

T;T

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.82

.;T

M_CAP

Benign

0.070

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-0.34

MutationAssessor

Benign

0.45

N;N

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.31

N;N

REVEL

Benign

0.26

Sift

Benign

0.57

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.0010

B;B

Vest4

0.29

MutPred

0.35

Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);

MVP

0.85

ClinPred

0.48

GERP RS

3.7

Varity_R

0.27

gMVP

0.79

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