rs1554982299

chr11-31789981-GAACTTGA-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PP5_Moderate

The NM_001368894.2(PAX6):c.1257_1263del(p.Gln420ProfsTer117) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 20)
• Consequence: PAX6 NM_001368894.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.51

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]

ELP4 (HGNC:1171): (elongator acetyltransferase complex subunit 4) This gene encodes a component of the six subunit elongator complex, a histone acetyltransferase complex that associates directly with RNA polymerase II during transcriptional elongation. The human gene can partially complement sensitivity phenotypes of yeast ELP4 deletion mutants. This gene has also been associated with Rolandic epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PP5: Variant 11-31789981-GAACTTGA-G is Pathogenic according to our data. Variant chr11-31789981-GAACTTGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 460457.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX6	NM_001368894.2	c.1257_1263del	p.Gln420ProfsTer117	frameshift_variant	14/14	ENST00000640368.2
ELP4	NM_019040.5	c.*6459_*6465del		3_prime_UTR_variant	10/10	ENST00000640961.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX6	ENST00000640368.2	c.1257_1263del	p.Gln420ProfsTer117	frameshift_variant	14/14	5	NM_001368894.2
ELP4	ENST00000640961.2	c.*6459_*6465del		3_prime_UTR_variant	10/10	1	NM_019040.5	P3

Frequencies

GnomAD3 genomes Cov.: 20

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 20

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2017

This sequence change deletes 7 nucleotides from the PAX6 mRNA resulting in a frameshift p.Gln406Profs*117). This is not anticipated to result in nonsense mediated decay but it is expected to disrupt the last 18 amino acids of the PAX6 protein and extend it by an additional 100 amino acids. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PAX6-related disease.  However similar C-terminal extensions (p.Pro419Glnfs*106 and p.Asp413Glufs*112) have been reported in individuals affected with aniridia (PMID: 26661695, 12731001). For these reasons, this variant has been classified as Pathogenic. An amino acid that is disrupted by this frameshift variant, p.Gln422, has been shown to be functionally important. Experimental studies have shown that an amino acid substitution at codon 422 (p.Gln422Arg) disrupts the DNA and protein binding ability of the PAX6 protein (PMID:11309364, 16098226). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554982299; hg19: chr11-31811529;