rs121907921

Variant names:

• chr11-31801893-A-C
• rs121907921
• NM_001368894.2:c.161T>G

Your query was ambiguous. Multiple possible variants found:

• chr11-31801893-A-C
• chr11-31801893-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 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
• Publications: 0 publications found

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]

PAX6 Gene-Disease associations (from GenCC):

• aniridia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• PAX6-related ocular dysgenesis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Peters anomaly

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• coloboma, ocular, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• diabetes mellitus

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• aniridia-cerebellar ataxia-intellectual disability syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• foveal hypoplasia-presenile cataract syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated aniridia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated optic nerve hypoplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant keratitis

  Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 6 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 VariationId is 3473.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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, diabetes mellitus, aniridia-cerebellar ataxia-intellectual disability syndrome, foveal hypoplasia-presenile cataract syndrome, aniridia 1, PAX6-related ocular dysgenesis, coloboma, ocular, autosomal dominant, isolated optic nerve hypoplasia, autosomal dominant keratitis, isolated aniridia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX6	NM_001368894.2	c.161T>G	p.Val54Gly	missense_variant	Exon 6 of 14	ENST00000640368.2	NP_001355823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000640368.2	c.161T>G	p.Val54Gly	missense_variant	Exon 6 of 14	5	NM_001368894.2	ENSP00000492024.1

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

Mar 09, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	.;.;.;.;.;.;.;.;T;T;T;T;T;T;T;T;T;T;T;T
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
PhyloP100		8.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.83	.;.;N;N;.;N;.;.;.;.;.;N;.;N;.;.;.;.;N;.
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	.;.;D;D;.;D;.;.;.;.;.;D;.;D;.;.;.;.;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
Mutation Taster		=2/98	disease causing

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

Other links and lift over

dbSNP: rs121907921; hg19: chr11-31823441;