rs121907922

Positions:

• chr11-31789935-T-A
• chr11-31789935-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM4 PP5_Very_Strong

The NM_001368894.2(PAX6):​c.1310A>T​(p.Ter437LeuextTer14) variant causes a stop lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PAX6 NM_001368894.2 stop_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 3.85

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_001368894.2 Downstream stopcodon found after 129 codons.
• PP5: Variant 11-31789935-T-A is Pathogenic according to our data. Variant chr11-31789935-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-31789935-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX6	NM_001368894.2	c.1310A>T	p.Ter437LeuextTer14	stop_lost	14/14	ENST00000640368.2
ELP4	NM_019040.5	c.*6411T>A		3_prime_UTR_variant	10/10	ENST00000640961.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX6	ENST00000640368.2	c.1310A>T	p.Ter437LeuextTer14	stop_lost	14/14	5	NM_001368894.2
ELP4	ENST00000640961.2	c.*6411T>A		3_prime_UTR_variant	10/10	1	NM_019040.5	P3

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1295908 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 648964

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 27

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Mar 15, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2021	Normal stop codon changed to a Leucine codon, leading to the addition of 14 amino acids at the C-terminus; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18494745, 20132240, 28321846, 21850189, 25555363, 22204637, 16098226, 6330922, 18494744, 16199712, 22361317, 28698011, 18241071, 10477494, 11309364, 26661695, 12552561, 27431685, 29618921, 29367200, 32360764, 33594928, 27535533, 34101622, 33726816, 32467297) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PAX6: PP1:Strong, PM2, PM4, PS4:Moderate, PM6:Supporting, PP4 -

Aniridia 1 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Wessex Regional Genetics Laboratory, Salisbury District Hospital	Aug 15, 2019	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Genetic Epidemiology, Research Centre for Medical Genetics	-	- -

Hypertelorism;C0028738:Nystagmus;C3665347:Visual impairment Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Clinical Genetics and Genomics, Karolinska University Hospital

Mar 29, 2018

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2023

This sequence change disrupts the translational stop signal of the PAX6 mRNA. It is expected to extend the length of the PAX6 protein by 14 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This protein extension has been observed in individual(s) with aniridia (PMID: 11309364, 12552561, 27431685, 28321846, 29618921). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as c.1290 A>T and X437L. ClinVar contains an entry for this variant (Variation ID: 3474). For these reasons, this variant has been classified as Pathogenic. -

Congenital ocular coloboma;C0155299:Coloboma of optic nerve;C0206115:11p partial monosomy syndrome;C0344542:Aniridia 1;C0344559:Irido-corneo-trabecular dysgenesis;C1833797:Isolated optic nerve hypoplasia;C1835698:Autosomal dominant keratitis;C3805604:Foveal hypoplasia 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	17
DANN	Uncertain	0.99
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	2.9e-8	A;A;A;A;A;A;A;A;A;A;A
GERP RS		5.0

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

LitVar

Other links and lift over

dbSNP: rs121907922; hg19: chr11-31811483; COSMIC: COSV53794040; COSMIC: COSV53794040;