NM_005029.4:c.657_658insCCAGACCCTGCAGGGCC

Variant names:

• chr10-102230765-C-CGGCCCTGCAGGGTCTGG
• NM_005029.4:c.657_658insCCAGACCCTGCAGGGCC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_005029.4(PITX3):​c.657_658insCCAGACCCTGCAGGGCC​(p.Gly220ProfsTer95) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PITX3 NM_005029.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.214

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 6 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 0.277 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX3	NM_005029.4	c.657_658insCCAGACCCTGCAGGGCC	p.Gly220ProfsTer95	frameshift_variant	Exon 4 of 4	ENST00000370002.8	NP_005020.1
PITX3	XM_047425352.1	c.657_658insCCAGACCCTGCAGGGCC	p.Gly220ProfsTer95	frameshift_variant	Exon 3 of 3		XP_047281308.1
GBF1	NM_001391923.1	c.-161_-160insGCCCTGCAGGGTCTGGG		5_prime_UTR_variant	Exon 1 of 40		NP_001378852.1
GBF1	NM_001391924.1	c.-299_-298insGCCCTGCAGGGTCTGGG		5_prime_UTR_variant	Exon 1 of 41		NP_001378853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITX3	ENST00000370002.8	c.657_658insCCAGACCCTGCAGGGCC	p.Gly220ProfsTer95	frameshift_variant	Exon 4 of 4	1	NM_005029.4	ENSP00000359019.3

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

Jul 12, 2021

Invitae

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a frameshift in the PITX3 gene (p.Gly220Profs*95). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 83 amino acid(s) of the PITX3 protein and extend the protein by 11 additional amino acid residues. 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 frameshift has been observed in individual(s) with congenital cataracts with or without anterior segment mesenchymal dysgenesis (PMID: 9620774, 15286169, 16272057, 16636655, 24555714). It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this frameshift affects PITX3 protein function (PMID: 17888164). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

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: chr10-103990522;