chr2-46581520-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002643.4(PIGF):​c.618G>T​(p.Trp206Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000335 in 1,611,564 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

PIGF
NM_002643.4 missense

Scores

5
11
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.09
Variant links:
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 made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PIGFNM_002643.4 linkuse as main transcriptc.618G>T p.Trp206Cys missense_variant 6/6 ENST00000281382.11 NP_002634.1
RHOQNM_012249.4 linkuse as main transcriptc.*437C>A 3_prime_UTR_variant 5/5 ENST00000238738.9 NP_036381.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PIGFENST00000281382.11 linkuse as main transcriptc.618G>T p.Trp206Cys missense_variant 6/61 NM_002643.4 ENSP00000281382 P1Q07326-1
RHOQENST00000238738.9 linkuse as main transcriptc.*437C>A 3_prime_UTR_variant 5/51 NM_012249.4 ENSP00000238738 P1

Frequencies

GnomAD3 genomes
AF:
0.000217
AC:
33
AN:
152174
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000748
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:
0.00
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.0000241
AC:
6
AN:
249180
Hom.:
0
AF XY:
0.0000297
AC XY:
4
AN XY:
134896
show subpopulations
Gnomad AFR exome
AF:
0.000309
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000137
AC:
20
AN:
1459272
Hom.:
0
Cov.:
30
AF XY:
0.0000110
AC XY:
8
AN XY:
725974
show subpopulations
Gnomad4 AFR exome
AF:
0.000419
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000498
GnomAD4 genome
AF:
0.000223
AC:
34
AN:
152292
Hom.:
0
Cov.:
32
AF XY:
0.000242
AC XY:
18
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.000770
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.000285
Hom.:
0
Bravo
AF:
0.000215
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 17, 2023The c.618G>T (p.W206C) alteration is located in exon 6 (coding exon 5) of the PIGF gene. This alteration results from a G to T substitution at nucleotide position 618, causing the tryptophan (W) at amino acid position 206 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.58
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Benign
0.20
T
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.89
D
M_CAP
Benign
0.0083
T
MetaRNN
Uncertain
0.62
D
MetaSVM
Uncertain
0.0054
D
MutationAssessor
Uncertain
2.9
M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.74
T
PROVEAN
Uncertain
-2.4
N
REVEL
Uncertain
0.41
Sift
Uncertain
0.0030
D
Sift4G
Uncertain
0.0070
D
Polyphen
1.0
D
Vest4
0.92
MutPred
0.68
Loss of MoRF binding (P = 0.0068);
MVP
0.65
MPC
4.9
ClinPred
0.46
T
GERP RS
5.5
Varity_R
0.65
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs559692231; hg19: chr2-46808659; API