10-102230766-GCCCAGGCCCTGCAGGGC-G

Position:

chr10-102230766-GCCCAGGCCCTGCAGGGC-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 12P and 4B. PVS1_StrongPP5_Very_StrongBS2

The ENST00000370002.8(PITX3):c.640_656del(p.Ala214ArgfsTer42) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000397 in 1,510,390 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

PITX3
ENST00000370002.8 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.70

Variant links:

Genes affected

PITX3 (HGNC:9006): (paired like homeodomain 3) This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. Members of this family act as transcription factors. This protein is involved in lens formation during eye development. Mutations of this gene have been associated with anterior segment mesenchymal dysgenesis and congenital cataracts. [provided by RefSeq, Jul 2008]

PITX3 links:

GBF1 (HGNC:):

GBF1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.

PP5

Variant 10-102230766-GCCCAGGCCCTGCAGGGC-G is Pathogenic according to our data. Variant chr10-102230766-GCCCAGGCCCTGCAGGGC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 468252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-102230766-GCCCAGGCCCTGCAGGGC-G is described in Lovd as [Likely_pathogenic]. Variant chr10-102230766-GCCCAGGCCCTGCAGGGC-G is described in Lovd as [Pathogenic]. Variant chr10-102230766-GCCCAGGCCCTGCAGGGC-G is described in Lovd as [Pathogenic]. Variant chr10-102230766-GCCCAGGCCCTGCAGGGC-G is described in Lovd as [Pathogenic]. Variant chr10-102230766-GCCCAGGCCCTGCAGGGC-G is described in Lovd as [Likely_pathogenic]. Variant chr10-102230766-GCCCAGGCCCTGCAGGGC-G is described in Lovd as [Pathogenic].

BS2

High AC in GnomAdExome4 at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PITX3	NM_005029.4 linkuse as main transcript	c.640_656del	p.Ala214ArgfsTer42	frameshift_variant	4/4	ENST00000370002.8	NP_005020.1
PITX3	XM_047425352.1 linkuse as main transcript	c.640_656del	p.Ala214ArgfsTer42	frameshift_variant	3/3		XP_047281308.1
GBF1	NM_001391923.1 linkuse as main transcript	c.-149_-133del		5_prime_UTR_variant	1/40		NP_001378852.1
GBF1	NM_001391924.1 linkuse as main transcript	c.-287_-271del		5_prime_UTR_variant	1/41		NP_001378853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PITX3	ENST00000370002.8 linkuse as main transcript	c.640_656del	p.Ala214ArgfsTer42	frameshift_variant	4/4	1	NM_005029.4	ENSP00000359019	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000747

AC:

AN:

107136

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

59242

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000564

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000138

Gnomad SAS exome

AF:

0.000114

Gnomad FIN exome

AF:

0.0000699

Gnomad NFE exome

AF:

0.0000775

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000412

AC:

AN:

1358426

Hom.:

AF XY:

0.0000433

AC XY:

AN XY:

669416

show subpopulations

Gnomad4 AFR exome

AF:

0.0000720

Gnomad4 AMR exome

AF:

0.000138

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000607

Gnomad4 SAS exome

AF:

0.0000405

Gnomad4 FIN exome

AF:

0.0000637

Gnomad4 NFE exome

AF:

0.0000376

Gnomad4 OTH exome

AF:

0.0000357

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151964

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74220

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000175

Hom.:

Bravo

AF:

0.0000416

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cataract 11 multiple types

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 19, 2024

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 21, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this premature translational stop signal affects PITX3 function (PMID: 30816539). This variant is present in population databases (no rsID available, gnomAD 0.01%). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 468252). This premature translational stop signal has been observed in individuals with congenital cataracts and/or Peter's anomalies (PMID: 30816539; Invitae). This sequence change creates a premature translational stop signal (p.Ala214Argfs*42) in the PITX3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 89 amino acid(s) of the PITX3 protein. -

Anterior segment dysgenesis 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Mar 31, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with PITX3-related anterior segment dysgenesis and cataracts. (I) 0108 - This gene is associated with both recessive and dominant disease. This gene has mostly been associated with dominant disease, although rare cases of recessive inheritance have been reported, with homozygous individuals having a more severe phenotype (PMID: 21836522, PMID: 30816539, PMID: 29405783). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 30816539). (I) 0115 - Variants in this gene are known to have variable expressivity. A wide range of interfamilial and intrafamilial phenotypic variability has been reported. (PMID: 29405783). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 (8 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is predicted to lose the OAR domain. The majority of reported pathogenic variants in PITX3 are predicted to result in the disruption of the OAR domain (PMID: 30894134). (I) 0702 - Other variants predicted to result in a truncated protein comparable to the one identified in this case have strong previous evidence for pathogenicity (ClinVar, PMID: 32830442). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in a homozygous patient with anterior segment dysgenesis and microphthalmia (PMID: 21836522) and heterozygous in at least four unrelated patients with congenital cataracts or Peters Anomaly (PMID: 30816539, PMID: 31848469, PMID: 33923544, PMID: 33304895). This variant has also been reported as a VUS in ClinVar. (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies indicated that the mutant protein retained a nuclear localisation pattern but resulted in decreased transactivation activity (PMID: 30816539). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over