rs121912545
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_182894.3(VSX2):c.679C>T(p.Arg227Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
VSX2
NM_182894.3 missense
NM_182894.3 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 2.58
Genes affected
VSX2 (HGNC:1975): (visual system homeobox 2) This gene encodes a homeobox protein originally described as a retina-specific transcription factor. Mutations in this gene are associated with microphthalmia, cataracts and iris abnormalities. [provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM1
?
In a domain CVC (size 53) in uniprot entity VSX2_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_182894.3
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.973
PP5
?
Variant 14-74259701-C-T is Pathogenic according to our data. Variant chr14-74259701-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14862.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VSX2 | NM_182894.3 | c.679C>T | p.Arg227Trp | missense_variant | 4/5 | ENST00000261980.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VSX2 | ENST00000261980.3 | c.679C>T | p.Arg227Trp | missense_variant | 4/5 | 1 | NM_182894.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152172Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251100Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135674
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461636Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727094
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74340
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Isolated microphthalmia 2 Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 14, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects VSX2 function (PMID: 23028343). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VSX2 protein function. ClinVar contains an entry for this variant (Variation ID: 14862). This missense change has been observed in individuals with microphthalmia (PMID: 15257456, 20414678). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121912545, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 227 of the VSX2 protein (p.Arg227Trp). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2004 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
Anophthalmia;C0026010:Microphthalmia Pathogenic:1
Pathogenic, no assertion criteria provided | research | Molecular Genetics Laboratory, Institute for Ophthalmic Research | Dec 13, 2017 | - - |
VSX2-related Microphthalmia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 15, 2024 | Variant summary: VSX2 c.679C>T (p.Arg227Trp) results in a non-conservative amino acid change located in the CVC domain (IPR023339) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251100 control chromosomes (gnomAD). c.679C>T has been reported in the literature in several homozygous individuals affected with VSX2-related Microphthalmia (Bar-Yosef_2004). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 15257456). ClinVar contains an entry for this variant (Variation ID: 14862). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Microphthalmia, isolated, with coloboma 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of phosphorylation at S229 (P = 0.0621);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at