rs121907919

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_001368894.2(PAX6):c.419T>A(p.Val140Asp) 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

PAX6
NM_001368894.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 8.70

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

aniridia 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
PAX6-related ocular dysgenesis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Peters anomaly
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
coloboma, ocular, autosomal dominant
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
diabetes mellitus
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
aniridia-cerebellar ataxia-intellectual disability syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
foveal hypoplasia-presenile cataract syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated aniridia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated optic nerve hypoplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal dominant keratitis
Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

PAX6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001368894.2

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the PAX6 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 75 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 2.8175 (below the threshold of 3.09). Trascript score misZ: 3.256 (above the threshold of 3.09). GenCC associations: The gene is linked to Peters anomaly, diabetes mellitus, aniridia-cerebellar ataxia-intellectual disability syndrome, foveal hypoplasia-presenile cataract syndrome, aniridia 1, PAX6-related ocular dysgenesis, coloboma, ocular, autosomal dominant, isolated optic nerve hypoplasia, autosomal dominant keratitis, isolated aniridia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 11-31800837-A-T is Pathogenic according to our data. Variant chr11-31800837-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX6	NM_001368894.2 link	c.419T>A	p.Val140Asp	missense_variant	Exon 8 of 14	ENST00000640368.2	NP_001355823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000640368.2 link	c.419T>A	p.Val140Asp	missense_variant	Exon 8 of 14	5	NM_001368894.2	ENSP00000492024.1		P26367-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aniridia 1;C0344559:Irido-corneo-trabecular dysgenesis

Pathogenic:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 126 of the PAX6 protein (p.Val126Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with aniridia (PMID: 9931324, 37217489). ClinVar contains an entry for this variant (Variation ID: 3471). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PAX6 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PAX6 function (PMID: 14744876, 27013732). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Aniridia, atypical

Pathogenic:1

Feb 01, 1999

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

PAX6-related ocular dysgenesis

Pathogenic:1

Jan 03, 2025

Clinical Genetics Laboratory, Region Ostergotland

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The NM_000280.6 c.377T>A variant was found in a proband with ocular symptoms inculding iris coloboma, myopia and nystagmus, and in addition mild intellectual disability. The variant is not found in population database (no frequency gnomAD v4.1.0). REVEL score for this missense variant is 0.934. The variant is in exon 7 in the DNA-binding paired domain (PD). The variant is found in three individuals with Aniridia (PMID:37217489, PMID:9931324). Based on this information, the following ACMG/AMP criteria were applied in classifying this variant: PM2_supp, PS4_mod, PP3_mod, PM1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.99

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

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.99

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

1.0

MutationAssessor

Uncertain

2.7

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

PhyloP100

8.7

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-5.8

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

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.97

MutPred

0.92

.;.;.;Gain of disorder (P = 0.0058);Gain of disorder (P = 0.0058);Gain of disorder (P = 0.0058);Gain of disorder (P = 0.0058);Gain of disorder (P = 0.0058);.;Gain of disorder (P = 0.0058);.;.;.;.;.;Gain of disorder (P = 0.0058);Gain of disorder (P = 0.0058);.;.;Gain of disorder (P = 0.0058);.;.;.;Gain of disorder (P = 0.0058);Gain of disorder (P = 0.0058);Gain of disorder (P = 0.0058);Gain of disorder (P = 0.0058);.;.;.;.;Gain of disorder (P = 0.0058);.;.;.;

MVP

1.0

MPC

2.5

ClinPred

1.0

GERP RS

4.3

Varity_R

0.97

gMVP

0.99

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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