rs1554982299

Variant names:

• chr11-31789981-GAACTTGA-G
• rs1554982299
• NM_001368894.2:c.1257_1263delTCAAGTT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Strong PS3 PP5_Moderate

The NM_001368894.2(PAX6):​c.1257_1263delTCAAGTT​(p.Gln420ProfsTer117) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000632658: 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).".

• 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
• Publications: 0 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]

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]

ELP4 Gene-Disease associations (from GenCC):

• aniridia 2

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Genomics England PanelApp
• ocular dysgenesis caused by defects in PAX6 regulation

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• aniridia 1

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 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 11 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000632658: 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).
• PP5: Variant 11-31789981-GAACTTGA-G is Pathogenic according to our data. Variant chr11-31789981-GAACTTGA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 460457.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001368894.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX6	NM_001368894.2	MANE Select	c.1257_1263delTCAAGTT	p.Gln420ProfsTer117	frameshift	Exon 14 of 14	NP_001355823.1	P26367-2
	ELP4	NM_019040.5	MANE Select	c.*6459_*6465delACTTGAA		3_prime_UTR	Exon 10 of 10	NP_061913.3
	PAX6	NM_001368910.2		c.1458_1464delTCAAGTT	p.Gln487ProfsTer117	frameshift	Exon 14 of 14	NP_001355839.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX6	ENST00000640368.2	TSL:5 MANE Select	c.1257_1263delTCAAGTT	p.Gln420ProfsTer117	frameshift	Exon 14 of 14	ENSP00000492024.1	P26367-2
	PAX6	ENST00000419022.6	TSL:1	c.1257_1263delTCAAGTT	p.Gln420ProfsTer117	frameshift	Exon 14 of 14	ENSP00000404100.1	P26367-2
	PAX6	ENST00000638914.3	TSL:1	c.1257_1263delTCAAGTT	p.Gln420ProfsTer117	frameshift	Exon 14 of 14	ENSP00000492315.2	P26367-2

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Aniridia 1;C0344559:Irido-corneo-trabecular dysgenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1554982299; hg19: chr11-31811529;