rs1131692284

Positions:

• chr11-31806411-T-C
• chr11-31806411-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_001368894.2(PAX6):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAX6 NM_001368894.2 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.77

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 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_001368894.2 (PAX6) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-31806411-T-C is Pathogenic according to our data. Variant chr11-31806411-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 430971.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX6	NM_001368894.2	c.1A>G	p.Met1?	start_lost	4/14	ENST00000640368.2	NP_001355823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000640368.2	c.1A>G	p.Met1?	start_lost	4/14	5	NM_001368894.2	ENSP00000492024

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Aniridia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory of Genetic Epidemiology, Research Centre for Medical Genetics

-

- -

Irido-corneo-trabecular dysgenesis Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Molecular Medicine, University of Pavia

Jul 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.46	.;.;.;T;T;T;T;T;.;T;.;.;.;.;.;.;.;T;.;.;T;.;T;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.
Eigen	Benign	-0.010
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;D;D;.;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PROVEAN	Benign	-1.1	.;.;N;.;.;.;N;N;N;.;.;.;N;.;.;.;.;N;.;.;.;.;N;.;N;.;N;.;N;.;N;.;.;.;.;N;.;D
REVEL	Uncertain	0.61
Sift	Benign	0.043	.;.;D;.;.;.;T;T;D;.;.;.;D;.;.;.;.;T;.;.;.;.;D;.;T;.;D;.;D;.;T;.;.;.;.;D;.;.
Sift4G	Benign	0.12	T;.;T;.;.;.;T;.;T;.;.;.;T;.;.;.;.;T;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.;.;.
Polyphen		0.0020	.;.;.;B;B;B;B;B;.;B;.;.;.;.;.;.;.;B;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.94
MutPred		1.0		Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);Loss of glycosylation at S6 (P = 0.2935);
MVP		1.0
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.47
gMVP		0.74

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: rs1131692284; hg19: chr11-31827959;