11-31806411-T-G

Position:

• chr11-31806411-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001368904.2(PAX6):​c.-277A>C variant causes a 5 prime UTR premature start codon gain 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_001368904.2 5_prime_UTR_premature_start_codon_gain
• 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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 11-31806411-T-G is Pathogenic according to our data. Variant chr11-31806411-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 430972.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>C	p.Met1?	initiator_codon_variant	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>C	p.Met1?	initiator_codon_variant	4/14	5	NM_001368894.2	ENSP00000492024.1

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

-

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2017

Different variants that also disrupt the initiation codon (c.1A>G, c.2T>A, c.2T>G) have been reported in  individuals affected with aniridia, and determined to be pathogenic (PMID: 10234503, 16712695, 28321846, 21850189, 26535646) For these reasons, this variant has been classified as Pathogenic. This variant has been reported in individuals affected with aniridia (PMID: 28321846, Invitae). ClinVar contains an entry for this variant (Variation ID: 430972). This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the PAX6 mRNA. The next in-frame methionine is located at codon 137. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Uncertain	0.46	.;.;.;T;T;T;T;T;.;T;.;.;.;.;.;.;.;T;.;.;T;.;T;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.
Eigen	Benign	-0.0026
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.95	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	0.95	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	Pathogenic	0.80	D
PROVEAN	Benign	-1.1	.;.;N;.;.;.;N;N;N;.;.;.;N;.;.;.;.;N;.;.;.;.;N;.;N;.;N;.;N;.;N;.;.;.;.;N;.;D
REVEL	Uncertain	0.59
Sift	Benign	0.055	.;.;T;.;.;.;T;T;T;.;.;.;T;.;.;.;.;T;.;.;.;.;T;.;T;.;T;.;T;.;T;.;.;.;.;T;.;.
Sift4G	Benign	0.50	T;.;T;.;.;.;T;.;T;.;.;.;T;.;.;.;.;T;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.;.;.
Polyphen		0.0	.;.;.;B;B;B;B;B;.;B;.;.;.;.;.;.;.;B;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.88
MutPred		0.99		Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);Gain of glycosylation at S6 (P = 0.29);
MVP		0.99
ClinPred		0.94	D
GERP RS		5.5
Varity_R		0.52
gMVP		0.66

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;