rs121907921

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_001368894.2(PAX6):​c.161T>G​(p.Val54Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

PAX6
NM_001368894.2 missense

Scores

7
6
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.87
Variant links:
Genes affected
PAX6 (HGNC:8620): (paired box 6) This gene encodes paired box protein Pax-6, one of many human homologs of the Drosophila melanogaster gene prd. In addition to a conserved paired box domain, a hallmark feature of this gene family, the encoded protein also contains a homeobox domain. Both domains are known to bind DNA and function as regulators of gene transcription. Activity of this protein is key in the development of neural tissues, particularly the eye. This gene is regulated by multiple enhancers located up to hundreds of kilobases distant from this locus. Mutations in this gene or in the enhancer regions can cause ocular disorders such as aniridia and Peter's anomaly. Use of alternate promoters and alternative splicing results in multiple transcript variants encoding different isoforms. Interestingly, inclusion of a particular alternate coding exon has been shown to increase the length of the paired box domain and alter its DNA binding specificity. Consequently, isoforms that carry the shorter paired box domain regulate a different set of genes compared to the isoforms carrying the longer paired box domain. [provided by RefSeq, Mar 2019]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PAX6. . Gene score misZ 2.8175 (greater than the threshold 3.09). Trascript score misZ 3.256 (greater than threshold 3.09). GenCC has associacion of gene with Peters anomaly, coloboma, ocular, autosomal dominant, coloboma of optic nerve, aniridia 1, PAX6-related ocular dysgenesis, foveal hypoplasia 1, foveal hypoplasia-presenile cataract syndrome, isolated aniridia, diabetes mellitus, aniridia-cerebellar ataxia-intellectual disability syndrome, autosomal dominant keratitis, isolated optic nerve hypoplasia.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PAX6NM_001368894.2 linkuse as main transcriptc.161T>G p.Val54Gly missense_variant 6/14 ENST00000640368.2 NP_001355823.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PAX6ENST00000640368.2 linkuse as main transcriptc.161T>G p.Val54Gly missense_variant 6/145 NM_001368894.2 ENSP00000492024 P26367-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMar 09, 2022Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; A different missense change at this residue in this alternate transcript (p.V54D; NM_001604.4) has been reported in the published literature in association with Peters anomaly, congenital cataract, Axenfeld anomaly, and/or foveal hypoplasia (Azuma et al., 1999) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.18
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Benign
0.11
.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.81
.;.;.;.;.;.;.;.;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP
Pathogenic
0.78
D
MetaRNN
Pathogenic
0.83
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-0.83
.;.;N;N;.;N;.;.;.;.;.;N;.;N;.;.;.;.;N;.
REVEL
Pathogenic
0.74
Sift
Pathogenic
0.0
.;.;D;D;.;D;.;.;.;.;.;D;.;D;.;.;.;.;T;.
Sift4G
Uncertain
0.0050
D;.;D;D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.
Vest4
0.62
MutPred
0.59
Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);
MVP
0.76
MPC
1.3
ClinPred
1.0
D
GERP RS
5.3
gMVP
0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-31823441; API