10-102230766-GCCCAGGCCCTGCAGGGC-GCCCAGGCCCTGCAGGGCCCCAGGCCCTGCAGGGC
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong
The NM_005029.4(PITX3):c.640_656dupGCCCTGCAGGGCCTGGG(p.Gly220ProfsTer95) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000736 in 1,358,438 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 INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 7.4e-7 ( 0 hom. )
Consequence
PITX3
NM_005029.4 frameshift
NM_005029.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.31
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 neuropathyInheritance: AD Classification: STRONG Submitted by: Franklin by Genoox
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ACMG classification
Classification was made for transcript
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 4 pathogenic variants in the truncated region.
PP5
Variant 10-102230766-G-GCCCAGGCCCTGCAGGGC is Pathogenic according to our data. Variant chr10-102230766-G-GCCCAGGCCCTGCAGGGC is described in ClinVar as Pathogenic. ClinVar VariationId is 468353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PITX3 | NM_005029.4 | MANE Select | c.640_656dupGCCCTGCAGGGCCTGGG | p.Gly220ProfsTer95 | frameshift | Exon 4 of 4 | NP_005020.1 | ||
| GBF1 | NM_001391923.1 | c.-149_-133dupCAGGGCCCCAGGCCCTG | 5_prime_UTR | Exon 1 of 40 | NP_001378852.1 | ||||
| GBF1 | NM_001391924.1 | c.-287_-271dupCAGGGCCCCAGGCCCTG | 5_prime_UTR | Exon 1 of 41 | NP_001378853.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| PITX3 | ENST00000370002.8 | TSL:1 MANE Select | c.640_656dupGCCCTGCAGGGCCTGGG | p.Gly220ProfsTer95 | frameshift | Exon 4 of 4 | ENSP00000359019.3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 7.36e-7 AC: 1AN: 1358438Hom.: 0 Cov.: 32 AF XY: 0.00000149 AC XY: 1AN XY: 669420 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
1
AN:
1358438
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
669420
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
27780
American (AMR)
AF:
AC:
0
AN:
28996
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
23066
East Asian (EAS)
AF:
AC:
0
AN:
32976
South Asian (SAS)
AF:
AC:
0
AN:
74148
European-Finnish (FIN)
AF:
AC:
0
AN:
47066
Middle Eastern (MID)
AF:
AC:
0
AN:
4894
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1063448
Other (OTH)
AF:
AC:
0
AN:
56064
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.325
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
ClinVar submissions as Germline
Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
3
-
-
not provided (3)
1
-
-
Anterior segment dysgenesis 1 (1)
1
-
-
ANTERIOR SEGMENT DYSGENESIS 1, MULTIPLE SUBTYPES (1)
1
-
-
Cataract 11 multiple types (1)
1
-
-
Cataract 11, posterior polar (1)
1
-
-
PITX3-related disorder (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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