rs121907926

Positions:

• chr11-31790722-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The NM_001368894.2(PAX6):​c.1213A>G​(p.Thr405Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAX6 NM_001368894.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.87

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PAX6. . Gene score misZ 2.8175 (greater than the threshold 3.09). Trascript score misZ 3.256 (greater than threshold 3.09). GenCC has associacion of gene with 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.
• PP5: Variant 11-31790722-T-C is Pathogenic according to our data. Variant chr11-31790722-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 3478.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.36112922). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX6	NM_001368894.2	c.1213A>G	p.Thr405Ala	missense_variant	13/14	ENST00000640368.2	NP_001355823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000640368.2	c.1213A>G	p.Thr405Ala	missense_variant	13/14	5	NM_001368894.2	ENSP00000492024

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Optic nerve aplasia, bilateral Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.35	.;.;.;T;T;T;T;T;.;T;.;.;.;.;.;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.72	.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;T;.;.;.;.;.;T;T;T;T;T;T;.;T;.;T;.;T;T;T;.;T;T;T;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	-0.075	.;.;.;N;N;N;N;N;.;N;.;.;.;.;.;.;N;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.63	.;.;N;.;.;.;N;N;N;.;.;N;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.44
Sift	Benign	0.32	.;.;T;.;.;.;T;T;T;.;.;T;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.62	T;.;T;.;.;.;T;.;T;.;.;T;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.
Polyphen		0.0010	.;.;.;B;B;B;B;B;.;B;.;.;.;.;.;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.27
MutPred		0.69		.;.;.;Loss of glycosylation at T391 (P = 0.0229);Loss of glycosylation at T391 (P = 0.0229);Loss of glycosylation at T391 (P = 0.0229);Loss of glycosylation at T391 (P = 0.0229);Loss of glycosylation at T391 (P = 0.0229);.;Loss of glycosylation at T391 (P = 0.0229);.;.;.;.;.;.;Loss of glycosylation at T391 (P = 0.0229);.;.;.;.;.;.;.;Loss of glycosylation at T391 (P = 0.0229);.;.;.;.;Loss of glycosylation at T391 (P = 0.0229);Loss of glycosylation at T391 (P = 0.0229);.;.;Loss of glycosylation at T391 (P = 0.0229);.;.;.;Loss of glycosylation at T391 (P = 0.0229);.;.;
MVP		0.98
MPC		0.89
ClinPred		0.82	D
GERP RS		1.2
Varity_R		0.13
gMVP		0.68

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: rs121907926; hg19: chr11-31812270;