rs1057517785

Positions:

• chr11-31793521-G-A
• chr11-31793521-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001368894.2(PAX6):​c.991C>T​(p.Arg331Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PAX6 NM_001368894.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.31

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-31793521-G-A is Pathogenic according to our data. Variant chr11-31793521-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 372444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-31793521-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX6	NM_001368894.2	c.991C>T	p.Arg331Ter	stop_gained	12/14	ENST00000640368.2	NP_001355823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000640368.2	c.991C>T	p.Arg331Ter	stop_gained	12/14	5	NM_001368894.2	ENSP00000492024

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727248

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2021	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate that R317X results in reduced activation of reporter genes compared to wild type (Chauhan et al., 2004); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26661695, 12868034, 21850189, 19898691, 25525159, 14744876, 27381094, 8111379, 27081561, 29901133, 12634864, 32360764, 34101622, 21397818, 15020706) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PAX6: PVS1, PP1:Strong, PS2, PM2, PS4:Moderate, PS3:Supporting -

Aniridia 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Wessex Regional Genetics Laboratory, Salisbury District Hospital

Aug 15, 2019

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 08, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 372444). This premature translational stop signal has been observed in individuals with aniridia (PMID: 8111279, 19898691, 21397818, 22692063, 26661695). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg317*) in the PAX6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAX6 are known to be pathogenic (PMID: 12634864). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
Vest4		0.86
GERP RS		4.8

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: rs1057517785; hg19: chr11-31815069; COSMIC: COSV99570800; COSMIC: COSV99570800;