11-31801561-G-C

Variant names:

• chr11-31801561-G-C
• rs121907928
• NM_001368894.2:c.399C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_001368894.2(PAX6):​c.399C>G​(p.Ser133Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAX6 NM_001368894.2 missense, splice_region
• Scores: Splicing: ADA: 0.001534
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.57

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
• PP2: Missense variant in the PAX6 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 75 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 2.8175 (below the threshold of 3.09). Trascript score misZ: 3.256 (above the threshold of 3.09). GenCC associations: The gene is linked to Peters anomaly, coloboma, ocular, autosomal dominant, coloboma of optic nerve, aniridia 1, PAX6-related ocular dysgenesis, foveal hypoplasia 1, foveal hypoplasia-presenile cataract syndrome, isolated aniridia, diabetes mellitus, aniridia-cerebellar ataxia-intellectual disability syndrome, autosomal dominant keratitis, isolated optic nerve hypoplasia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 11-31801561-G-C is Pathogenic according to our data. Variant chr11-31801561-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 430991.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX6	NM_001368894.2	c.399C>G	p.Ser133Arg	missense_variant, splice_region_variant	Exon 7 of 14	ENST00000640368.2	NP_001355823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000640368.2	c.399C>G	p.Ser133Arg	missense_variant, splice_region_variant	Exon 7 of 14	5	NM_001368894.2	ENSP00000492024.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Aniridia 1 Pathogenic:1

-

Laboratory of Genetic Epidemiology, Research Centre for Medical Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;D;D;D;D;.;D;.;.;.;.;.;.;D;D;.;.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.98	.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;.;D;D;.;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	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	1.1	D
MutationAssessor	Pathogenic	3.2	.;.;.;M;M;M;M;M;.;M;.;.;.;.;.;.;M;M;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.3	.;.;D;.;.;.;D;D;D;.;.;D;.;.;.;.;D;.;.;D;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;.;D;.;.;.;D;D;D;.;.;D;.;.;.;.;D;.;.;D;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;.;D;.;.;.;D;.;D;.;.;D;.;.;.;.;D;.;.;D;.;.;.;.;.;.;.;.
Polyphen		1.0	.;.;.;D;D;D;D;D;.;D;.;.;.;.;.;.;D;D;.;.;.;.;.;.;.;.;.;.
Vest4		0.93
MutPred		0.95		.;.;.;Gain of MoRF binding (P = 0.0208);Gain of MoRF binding (P = 0.0208);Gain of MoRF binding (P = 0.0208);Gain of MoRF binding (P = 0.0208);Gain of MoRF binding (P = 0.0208);.;Gain of MoRF binding (P = 0.0208);.;.;.;.;.;Gain of MoRF binding (P = 0.0208);Gain of MoRF binding (P = 0.0208);Gain of MoRF binding (P = 0.0208);.;Gain of MoRF binding (P = 0.0208);Gain of MoRF binding (P = 0.0208);Gain of MoRF binding (P = 0.0208);Gain of MoRF binding (P = 0.0208);.;Gain of MoRF binding (P = 0.0208);.;.;.;
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.97
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0015
dbscSNV1_RF	Benign	0.38
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: rs121907928; hg19: chr11-31823109;