10-102230766-GCCCAGGCCCTGCAGGGC-G

Variant names:

• chr10-102230766-GCCCAGGCCCTGCAGGGC-G
• rs1411557416
• NM_005029.4:c.640_656delGCCCTGCAGGGCCTGGG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 16P and 4B. PVS1_Strong PS3 PP5_Very_Strong BS2

The NM_005029.4(PITX3):​c.640_656delGCCCTGCAGGGCCTGGG​(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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000644789: Experimental studies have shown that this premature translational stop signal affects PITX3 function (PMID:30816539)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: PITX3 NM_005029.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.70
• Publications: 9 publications found

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]

GBF1 Gene-Disease associations (from GenCC):

• axonal neuropathy

  Inheritance: AD Classification: STRONG Submitted by: Franklin by Genoox

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 7 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000644789: Experimental studies have shown that this premature translational stop signal affects PITX3 function (PMID: 30816539).; SCV005921884: Published functional studies demonstrate a damaging effect due to reduced transactivation of target genes as compared to wild-type. PMID:30816539; SCV005398134: "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)."
• PP5: Variant 10-102230766-GCCCAGGCCCTGCAGGGC-G is Pathogenic according to our data. Variant chr10-102230766-GCCCAGGCCCTGCAGGGC-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 468252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 56 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005029.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX3	NM_005029.4	MANE Select	c.640_656delGCCCTGCAGGGCCTGGG	p.Ala214ArgfsTer42	frameshift	Exon 4 of 4	NP_005020.1	O75364
	GBF1	NM_001391923.1		c.-149_-133delCAGGGCCCCAGGCCCTG		5_prime_UTR	Exon 1 of 40	NP_001378852.1	Q92538-2
	GBF1	NM_001391924.1		c.-287_-271delCAGGGCCCCAGGCCCTG		5_prime_UTR	Exon 1 of 41	NP_001378853.1	Q92538-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITX3	ENST00000370002.8	TSL:1 MANE Select	c.640_656delGCCCTGCAGGGCCTGGG	p.Ala214ArgfsTer42	frameshift	Exon 4 of 4	ENSP00000359019.3	O75364

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151964 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.0000747 AC: 8 AN: 107136 AF XY: 0.000118

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 FIN exome AF: 0.0000699

Gnomad NFE exome AF: 0.0000775

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000412 AC: 56 AN: 1358426 Hom.: 0 AF XY: 0.0000433 AC XY: 29 AN XY: 669416

African (AFR) AF: 0.0000720 AC: 2 AN: 27780

American (AMR) AF: 0.000138 AC: 4 AN: 28996

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23066

East Asian (EAS) AF: 0.0000607 AC: 2 AN: 32976

South Asian (SAS) AF: 0.0000405 AC: 3 AN: 74148

European-Finnish (FIN) AF: 0.0000637 AC: 3 AN: 47066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4894

European-Non Finnish (NFE) AF: 0.0000376 AC: 40 AN: 1063438

Other (OTH) AF: 0.0000357 AC: 2 AN: 56062

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151964 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74220

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000483 AC: 2 AN: 41404

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67938

Other (OTH) AF: 0.00 AC: 0 AN: 2082

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000175 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Anterior segment dysgenesis 1 (1)
1	-	-	Cataract 11 multiple types (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7
Mutation Taster		=63/137	disease causing (long InDel)

Splicing

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

Other links and lift over

dbSNP: rs1411557416; hg19: chr10-103990523;