2-46581572-G-A
Variant names:
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2
The NM_002643.4(PIGF):c.566C>T(p.Thr189Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,611,152 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T189R) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000033 ( 0 hom. )
Consequence
PIGF
NM_002643.4 missense
NM_002643.4 missense
Scores
2
8
9
Clinical Significance
Conservation
PhyloP100: 7.68
Publications
1 publications found
Genes affected
PIGF (HGNC:8962): (phosphatidylinositol glycan anchor biosynthesis class F) This gene encodes a protein involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor, a glycolipid containing three mannose molecules in its core backbone, is found on many blood cells where it serves to anchor proteins to the cell surface. The encoded protein and another GPI synthesis protein, PIGO, function in the transfer of ethanolaminephosphate to the third mannose in GPI. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]
RHOQ (HGNC:17736): (ras homolog family member Q) This gene encodes a member of the Rho family of small GTPases, which cycle between inactive GDP-bound and active GTP-bound states and function as molecular switches in signal transduction cascades. Rho proteins promote reorganization of the actin cytoskeleton and regulate cell shape, attachment, and motility. The encoded protein is an important signalling protein for sarcomere assembly and has been shown to play a significant role in the exocytosis of the solute carrier family 2, facilitated glucose transporter member 4 and other proteins, possibly acting as the signal that turns on the membrane fusion machinery. Three related pseudogene have been identified on chromosomes 2 and 14. [provided by RefSeq, Aug 2011]
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PIGF | ENST00000281382.11 | c.566C>T | p.Thr189Met | missense_variant | Exon 6 of 6 | 1 | NM_002643.4 | ENSP00000281382.6 | ||
| RHOQ | ENST00000238738.9 | c.*489G>A | 3_prime_UTR_variant | Exon 5 of 5 | 1 | NM_012249.4 | ENSP00000238738.4 |
Frequencies
GnomAD3 genomes 0.0000329 AC: 5AN: 152170Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
5
AN:
152170
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD2 exomes AF: 0.0000323 AC: 8AN: 247298 AF XY: 0.0000447 show subpopulations
GnomAD2 exomes
AF:
AC:
8
AN:
247298
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000329 AC: 48AN: 1458982Hom.: 0 Cov.: 30 AF XY: 0.0000331 AC XY: 24AN XY: 725784 show subpopulations
GnomAD4 exome
AF:
AC:
48
AN:
1458982
Hom.:
Cov.:
30
AF XY:
AC XY:
24
AN XY:
725784
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33384
American (AMR)
AF:
AC:
1
AN:
44692
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26110
East Asian (EAS)
AF:
AC:
2
AN:
39676
South Asian (SAS)
AF:
AC:
2
AN:
86128
European-Finnish (FIN)
AF:
AC:
0
AN:
53340
Middle Eastern (MID)
AF:
AC:
1
AN:
4130
European-Non Finnish (NFE)
AF:
AC:
40
AN:
1111368
Other (OTH)
AF:
AC:
2
AN:
60154
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.489
Heterozygous variant carriers
0
3
6
8
11
14
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome 0.0000329 AC: 5AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74332 show subpopulations
GnomAD4 genome
AF:
AC:
5
AN:
152170
Hom.:
Cov.:
32
AF XY:
AC XY:
3
AN XY:
74332
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41440
American (AMR)
AF:
AC:
0
AN:
15272
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5198
South Asian (SAS)
AF:
AC:
1
AN:
4824
European-Finnish (FIN)
AF:
AC:
1
AN:
10612
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
3
AN:
68038
Other (OTH)
AF:
AC:
0
AN:
2086
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
AF:
AC:
1
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Aug 10, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The c.566C>T (p.T189M) alteration is located in exon 6 (coding exon 5) of the PIGF gene. This alteration results from a C to T substitution at nucleotide position 566, causing the threonine (T) at amino acid position 189 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
PhyloP100
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Loss of sheet (P = 0.0315);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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