chr10-102230661-G-T

Position:

• chr10-102230661-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The ENST00000370002.8(PITX3):​c.762C>A​(p.Tyr254*) variant causes a stop gained change. 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PITX3 ENST00000370002.8 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.98

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]

GBF1 (HGNC:4181): (golgi brefeldin A resistant guanine nucleotide exchange factor 1) This gene encodes a member of the Sec7 domain family. The encoded protein is a guanine nucleotide exchange factor that regulates the recruitment of proteins to membranes by mediating GDP to GTP exchange. The encoded protein is localized to the Golgi apparatus and plays a role in vesicular trafficking by activating ADP ribosylation factor 1. The encoded protein has also been identified as an important host factor for viral replication. Multiple transcript variants have been observed for this gene. [provided by RefSeq, Dec 2010]

ACMG classification

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. Fraction of 0.162 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-102230661-G-T is Pathogenic according to our data. Variant chr10-102230661-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 620191.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PITX3	NM_005029.4	c.762C>A	p.Tyr254*	stop_gained	4/4	ENST00000370002.8	NP_005020.1
PITX3	XM_047425352.1	c.762C>A	p.Tyr254*	stop_gained	3/3		XP_047281308.1
GBF1	NM_001391923.1	c.-266G>T		5_prime_UTR_variant	1/40		NP_001378852.1
GBF1	NM_001391924.1	c.-404G>T		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	c.762C>A	p.Tyr254*	stop_gained	4/4	1	NM_005029.4	ENSP00000359019.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

PITX3-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 26, 2024

The PITX3 c.762C>A variant is predicted to result in premature protein termination (p.Tyr254*). This variant occurs within the terminal exon of PITX3 and truncates the protein by 49 amino acids. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. A nonsense variant downstream of p.Tyr254 has been reported in the heterozygous state in a patient with pediatric cataracts (Patient 23139 in Jackson et al. 2020. PubMed ID: 32830442). Based on this evidence, we interpret the c.762C>A (p.Tyr254*) variant as likely pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 11, 2018

The Y254X variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Y254X variant is not observed in large population cohorts (Lek et al., 2016). The Y254X nonsense variant in the PITX3 gene is predicted to cause loss of normal protein function through protein truncation. Specifically, the last 49 amino acids are predicted to be lost. This variant is interpreted to be likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.78	D
MutationTaster	Benign	1.0	A;D
Vest4		0.91
GERP RS		3.3

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: rs1564991147; hg19: chr10-103990418;