10-102230682-C-CGCG

Variant names:

• chr10-102230682-C-CGCG
• rs749538425
• NM_005029.4:c.738_740dupCGC

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP3 BS1_Supporting BS2

The NM_005029.4(PITX3):​c.738_740dupCGC​(p.Ala247dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.000537 in 1,578,622 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00057 (0 hom.)
• Consequence: PITX3 NM_005029.4 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.42

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_benign. Variant got -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005029.4
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000243 (37/152214) while in subpopulation NFE AF= 0.000382 (26/67980). AF 95% confidence interval is 0.000267. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITX3	NM_005029.4	c.738_740dupCGC	p.Ala247dup	disruptive_inframe_insertion	Exon 4 of 4	ENST00000370002.8	NP_005020.1
PITX3	XM_047425352.1	c.738_740dupCGC	p.Ala247dup	disruptive_inframe_insertion	Exon 3 of 3		XP_047281308.1
GBF1	NM_001391923.1	c.-230_-228dupGGC		5_prime_UTR_variant	Exon 1 of 40		NP_001378852.1
GBF1	NM_001391924.1	c.-368_-366dupGGC		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.738_740dupCGC	p.Ala247dup	disruptive_inframe_insertion	Exon 4 of 4	1	NM_005029.4	ENSP00000359019.3

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152100 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

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: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000256 AC: 45 AN: 175826 Hom.: 0 AF XY: 0.000230 AC XY: 22 AN XY: 95526

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000275

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000407

Gnomad FIN exome AF: 0.0000606

Gnomad NFE exome AF: 0.000469

Gnomad OTH exome AF: 0.000218

GnomAD4 exome AF: 0.000568 AC: 810 AN: 1426408 Hom.: 0 Cov.: 32 AF XY: 0.000536 AC XY: 379 AN XY: 706706

Gnomad4 AFR exome AF: 0.000153

Gnomad4 AMR exome AF: 0.000234

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000244

Gnomad4 FIN exome AF: 0.0000600

Gnomad4 NFE exome AF: 0.000708

Gnomad4 OTH exome AF: 0.000271

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74430

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2024

This variant, c.738_740dup, results in the insertion of 1 amino acid(s) of the PITX3 protein (p.Ala250dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs775510715, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PITX3-related conditions. ClinVar contains an entry for this variant (Variation ID: 665913). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs749538425; hg19: chr10-103990439;