10-102230785-C-CCA

Position:

• chr10-102230785-C-CCA

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.637_638insTG​(p.Gly213ValfsTer97) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PITX3 ENST00000370002.8 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.690

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:):

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. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-102230785-C-CCA is Pathogenic according to our data. Variant chr10-102230785-C-CCA is described in ClinVar as [Pathogenic]. Clinvar id is 1456216.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.637_638insTG	p.Gly213ValfsTer97	frameshift_variant	4/4	ENST00000370002.8	NP_005020.1
PITX3	XM_047425352.1	c.637_638insTG	p.Gly213ValfsTer97	frameshift_variant	3/3		XP_047281308.1
GBF1	NM_001391923.1	c.-141_-140dup		5_prime_UTR_variant	1/40		NP_001378852.1
GBF1	NM_001391924.1	c.-279_-278dup		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.637_638insTG	p.Gly213ValfsTer97	frameshift_variant	4/4	1	NM_005029.4	ENSP00000359019	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 14, 2021

For these reasons, this variant has been classified as Pathogenic. This variant results in an extension of the PITX3 protein. Other variant(s) that result in a similarly extended protein product (p.Gly220Profs*95) have been determined to be pathogenic (PMID: 9620774, 15286169, 24555714, 29405783). This suggests that these extensions are likely to be causative of disease. This variant has not been reported in the literature in individuals with PITX3-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change results in a frameshift in the PITX3 gene (p.Gly213Valfs*97). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 90 amino acid(s) of the PITX3 protein and extend the protein by 6 additional amino acid residues. -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr10-103990542;