11-31790710-C-T

Variant names:

• chr11-31790710-C-T
• rs1131692318
• NM_001368894.2:c.1225G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• 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
• Publications: 1 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• 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: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 11-31790710-C-T is Pathogenic according to our data. Variant chr11-31790710-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1459449.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX6	NM_001368894.2	c.1225G>A	p.Gly409Arg	missense_variant, splice_region_variant	Exon 13 of 14	ENST00000640368.2	NP_001355823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000640368.2	c.1225G>A	p.Gly409Arg	missense_variant, splice_region_variant	Exon 13 of 14	5	NM_001368894.2	ENSP00000492024.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Aniridia 1;C0344559:Irido-corneo-trabecular dysgenesis Pathogenic:1

Jan 03, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	33
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	D
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	D
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	D
MutationAssessor	Uncertain	2.8	.;.;.;M;M;M;M;M;.;M;.;.;.;.;.;.;M;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		7.5
PrimateAI	Pathogenic	0.91	D
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	D
GERP RS		6.0
Varity_R		0.77
gMVP		0.91
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs1131692318; hg19: chr11-31812258;