14-56801988-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM1BP4_ModerateBP6BS1BS2

The NM_021728.4(OTX2):​c.641C>A​(p.Thr214Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000381 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.00020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00040 ( 0 hom. )

Consequence

OTX2
NM_021728.4 missense

Scores

1
5
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 9.78
Variant links:
Genes affected
OTX2 (HGNC:8522): (orthodenticle homeobox 2) This gene encodes a member of the bicoid subfamily of homeodomain-containing transcription factors. The encoded protein acts as a transcription factor and plays a role in brain, craniofacial, and sensory organ development. The encoded protein also influences the proliferation and differentiation of dopaminergic neuronal progenitor cells during mitosis. Mutations in this gene cause syndromic microphthalmia 5 (MCOPS5) and combined pituitary hormone deficiency 6 (CPHD6). This gene is also suspected of having an oncogenic role in medulloblastoma. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Pseudogenes of this gene are known to exist on chromosomes two and nine. [provided by RefSeq, Jul 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PM1
In a chain Homeobox protein OTX2 (size 288) in uniprot entity OTX2_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_021728.4
BP4
Computational evidence support a benign effect (MetaRNN=0.20600048).
BP6
Variant 14-56801988-G-T is Benign according to our data. Variant chr14-56801988-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288894.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0004 (585/1461892) while in subpopulation NFE AF= 0.000495 (550/1112010). AF 95% confidence interval is 0.00046. There are 0 homozygotes in gnomad4_exome. There are 280 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
OTX2NM_021728.4 linkc.641C>A p.Thr214Asn missense_variant 5/5 ENST00000672264.2 NP_068374.1 P32243-2F1T0D1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
OTX2ENST00000672264.2 linkc.641C>A p.Thr214Asn missense_variant 5/5 NM_021728.4 ENSP00000500115.1 P32243-2

Frequencies

GnomAD3 genomes
AF:
0.000197
AC:
30
AN:
152160
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.000353
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000255
AC:
64
AN:
251460
Hom.:
0
AF XY:
0.000235
AC XY:
32
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.0000615
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:
0.000528
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.000400
AC:
585
AN:
1461892
Hom.:
0
Cov.:
32
AF XY:
0.000385
AC XY:
280
AN XY:
727246
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:
0.0000749
Gnomad4 NFE exome
AF:
0.000495
Gnomad4 OTH exome
AF:
0.000513
GnomAD4 genome
AF:
0.000197
AC:
30
AN:
152160
Hom.:
0
Cov.:
33
AF XY:
0.000121
AC XY:
9
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000353
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000355
Hom.:
0
Bravo
AF:
0.000166
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000305
AC:
37
EpiCase
AF:
0.000436
EpiControl
AF:
0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jul 07, 2016- -
Anophthalmia-microphthalmia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 18, 2024This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 206 of the OTX2 protein (p.Thr206Asn). This variant is present in population databases (rs150982073, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with OTX2-related conditions. ClinVar contains an entry for this variant (Variation ID: 288894). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -
Syndromic microphthalmia type 5 Benign:1
Likely benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Pituitary hormone deficiency, combined, 6 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJan 10, 2023This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
22
DANN
Benign
0.96
DEOGEN2
Uncertain
0.60
.;D;D;.
Eigen
Benign
0.066
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;.;D;D
M_CAP
Benign
0.023
T
MetaRNN
Benign
0.21
T;T;T;T
MetaSVM
Benign
-0.40
T
MutationAssessor
Benign
0.0
.;N;N;.
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
-0.99
N;N;N;N
REVEL
Benign
0.21
Sift
Uncertain
0.015
D;D;D;D
Sift4G
Benign
0.12
T;T;T;.
Polyphen
0.083
.;B;B;.
Vest4
0.60
MVP
0.54
MPC
0.062
ClinPred
0.12
T
GERP RS
4.6
Varity_R
0.25
gMVP
0.61

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.

Other links and lift over

dbSNP: rs150982073; hg19: chr14-57268706; API