4-54274845-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_006206.6(PDGFRA):​c.1658C>T​(p.Pro553Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

PDGFRA
NM_006206.6 missense

Scores

14
3
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.83
Variant links:
Genes affected
PDGFRA (HGNC:8803): (platelet derived growth factor receptor alpha) This gene encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. These growth factors are mitogens for cells of mesenchymal origin. The identity of the growth factor bound to a receptor monomer determines whether the functional receptor is a homodimer or a heterodimer, composed of both platelet-derived growth factor receptor alpha and beta polypeptides. Studies suggest that this gene plays a role in organ development, wound healing, and tumor progression. Mutations in this gene have been associated with idiopathic hypereosinophilic syndrome, somatic and familial gastrointestinal stromal tumors, and a variety of other cancers. [provided by RefSeq, Mar 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.89
BS2
High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PDGFRANM_006206.6 linkc.1658C>T p.Pro553Leu missense_variant 12/23 ENST00000257290.10 NP_006197.1 P16234-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PDGFRAENST00000257290.10 linkc.1658C>T p.Pro553Leu missense_variant 12/231 NM_006206.6 ENSP00000257290.5 P16234-1
ENSG00000282278ENST00000507166.5 linkc.1018-80C>T intron_variant 2 ENSP00000423325.1 A0A0B4J203
PDGFRAENST00000509092.5 linkn.1476C>T non_coding_transcript_exon_variant 11/151
PDGFRAENST00000509490.5 linkn.1658C>T non_coding_transcript_exon_variant 12/181 ENSP00000424218.1 P16234-3

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152086
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461844
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152086
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74276
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Idiopathic hypereosinophilic syndrome;C5193005:Polyps, multiple and recurrent inflammatory fibroid, gastrointestinal Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 15, 2022- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 10, 2022Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Gastrointestinal stromal tumor Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 11, 2024This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 553 of the PDGFRA protein (p.Pro553Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PDGFRA-related conditions. ClinVar contains an entry for this variant (Variation ID: 407380). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PDGFRA protein function. 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. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 06, 2023The p.P553L variant (also known as c.1658C>T), located in coding exon 11 of the PDGFRA gene, results from a C to T substitution at nucleotide position 1658. The proline at codon 553 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.43
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.62
D
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D
M_CAP
Benign
0.074
D
MetaRNN
Pathogenic
0.89
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.6
H
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-8.8
D
REVEL
Pathogenic
0.71
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.83
MutPred
0.58
Loss of methylation at K550 (P = 0.038);
MVP
0.92
MPC
1.1
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.60
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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: rs1060501502; hg19: chr4-55141012; COSMIC: COSV57267051; COSMIC: COSV57267051; API