rs121907921

chr11-31801893-A-Cchr11-31801893-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP3

The NM_001368894.2(PAX6):c.161T>G(p.Val54Gly) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V54D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAX6 NM_001368894.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.87

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001368894.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-31801893-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 3473.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant where missense usually causes diseases, PAX6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX6	NM_001368894.2	c.161T>G	p.Val54Gly	missense_variant	6/14	ENST00000640368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX6	ENST00000640368.2	c.161T>G	p.Val54Gly	missense_variant	6/14	5	NM_001368894.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 2022

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; A different missense change at this residue in this alternate transcript (p.V54D; NM_001604.4) has been reported in the published literature in association with Peters anomaly, congenital cataract, Axenfeld anomaly, and/or foveal hypoplasia (Azuma et al., 1999) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.83	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
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
Sift4G	Uncertain	0.0050	D;.;D;D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.
Vest4		0.62
MutPred		0.59		Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);
MVP		0.76
MPC		1.3
ClinPred		1.0	D
GERP RS		5.3
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-31823441;