11-31790710-C-T

Position:

chr11-31790710-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_ModeratePP5_Moderate

The NM_001368894.2(PAX6):c.1225G>A(p.Gly409Arg) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

PAX6
NM_001368894.2 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.50

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]

PAX6 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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). The gene has 75 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. GenCC has associacion of the 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, 0.874

PP5

Variant 11-31790710-C-T is Pathogenic according to our data. Variant chr11-31790710-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1459449.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX6	NM_001368894.2 link	c.1225G>A	p.Gly409Arg	missense_variant, splice_region_variant	13/14	ENST00000640368.2	NP_001355823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000640368.2 link	c.1225G>A	p.Gly409Arg	missense_variant, splice_region_variant	13/14	5	NM_001368894.2	ENSP00000492024.1		P26367-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Aniridia 1;C0344559:Irido-corneo-trabecular dysgenesis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 03, 2021

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.1183G nucleotide in the PAX6 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 7666404). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with aniridia (PMID: 21850189, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 395 of the PAX6 protein (p.Gly395Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 12, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

.;.;.;D;D;D;D;D;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;.;.;.;.;.;D;D;D;D;D;D;.;D;.;D;.;D;D;D;.;D;D;D;D

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.87

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Uncertain

2.8

.;.;.;M;M;M;M;M;.;M;.;.;.;.;.;.;M;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-4.8

.;.;D;.;.;.;D;D;D;.;.;D;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

.;.;D;.;.;.;D;D;D;.;.;D;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.

Sift4G

Uncertain

0.0030

D;.;D;.;.;.;D;.;D;.;.;D;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.

Polyphen

0.89

.;.;.;P;P;P;P;P;.;P;.;.;.;.;.;.;P;.;.;.;.;.;.;.;P;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.80

MutPred

0.49

.;.;.;Gain of catalytic residue at G395 (P = 0.0148);Gain of catalytic residue at G395 (P = 0.0148);Gain of catalytic residue at G395 (P = 0.0148);Gain of catalytic residue at G395 (P = 0.0148);Gain of catalytic residue at G395 (P = 0.0148);.;Gain of catalytic residue at G395 (P = 0.0148);.;.;.;.;.;.;Gain of catalytic residue at G395 (P = 0.0148);.;.;.;.;.;.;.;Gain of catalytic residue at G395 (P = 0.0148);.;.;.;.;Gain of catalytic residue at G395 (P = 0.0148);Gain of catalytic residue at G395 (P = 0.0148);.;.;Gain of catalytic residue at G395 (P = 0.0148);.;.;.;Gain of catalytic residue at G395 (P = 0.0148);.;.;

MVP

0.95

MPC

2.2

ClinPred

1.0

GERP RS

6.0

Varity_R

0.77

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.34

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over