rs121907922

Variant names:

• chr11-31789935-T-A
• rs121907922
• NM_001368894.2:c.1310A>T
• PAX6 p.Ter437Leuext*?

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001368911.2(PAX6):​c.1162A>T​(p.Lys388*) variant causes a stop gained 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_001368911.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 3.85
• Publications: 21 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 14 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. Fraction of 0.208 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-31789935-T-A is Pathogenic according to our data. Variant chr11-31789935-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001368911.2. 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.1310A>T	p.Ter437Leuext*?	stop_lost	Exon 14 of 14	NP_001355823.1	P26367-2
	ELP4	NM_019040.5	MANE Select	c.*6411T>A		3_prime_UTR	Exon 10 of 10	NP_061913.3
	PAX6	NM_001368911.2		c.1162A>T	p.Lys388*	stop_gained	Exon 10 of 10	NP_001355840.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX6	ENST00000640368.2	TSL:5 MANE Select	c.1310A>T	p.Ter437Leuext*?	stop_lost	Exon 14 of 14	ENSP00000492024.1	P26367-2
	PAX6	ENST00000419022.6	TSL:1	c.1310A>T	p.Ter437Leuext*?	stop_lost	Exon 14 of 14	ENSP00000404100.1	P26367-2
	PAX6	ENST00000638914.3	TSL:1	c.1310A>T	p.Ter437Leuext*?	stop_lost	Exon 14 of 14	ENSP00000492315.2	P26367-2

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

African (AFR) AF: 0.00 AC: 0 AN: 29606

American (AMR) AF: 0.00 AC: 0 AN: 39718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24218

East Asian (EAS) AF: 0.00 AC: 0 AN: 38306

South Asian (SAS) AF: 0.00 AC: 0 AN: 76500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5116

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 976296

Other (OTH) AF: 0.00 AC: 0 AN: 54536

GnomAD4 genome Cov.: 27

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
3	-	-	Aniridia 1 (3)
1	-	-	Aniridia 1;C0344559:Irido-corneo-trabecular dysgenesis (1)
1	-	-	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 (1)
1	-	-	Foveal hypoplasia 1 (1)
1	-	-	Hypertelorism;C0028738:Nystagmus;C3665347:Visual impairment (1)
1	-	-	Sporadic aniridia (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.8
Mutation Taster		=1/199	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121907922;

hg19: chr11-31811483;

COSMIC: COSV53794040;

COSMIC: COSV53794040;