4-54263898-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_006206.6(PDGFRA):ā€‹c.599C>Gā€‹(p.Thr200Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000555 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00079 ( 0 hom., cov: 32)
Exomes š‘“: 0.00053 ( 0 hom. )

Consequence

PDGFRA
NM_006206.6 missense

Scores

1
18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7O:1

Conservation

PhyloP100: 4.90
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 Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.008408099).
BP6
Variant 4-54263898-C-G is Benign according to our data. Variant chr4-54263898-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41800.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, not_provided=1, Benign=3}.
BS2
High AC in GnomAd4 at 121 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PDGFRANM_006206.6 linkc.599C>G p.Thr200Ser missense_variant 4/23 ENST00000257290.10 NP_006197.1 P16234-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PDGFRAENST00000257290.10 linkc.599C>G p.Thr200Ser missense_variant 4/231 NM_006206.6 ENSP00000257290.5 P16234-1
ENSG00000282278ENST00000507166.5 linkc.1018-11027C>G intron_variant 2 ENSP00000423325.1 A0A0B4J203

Frequencies

GnomAD3 genomes
AF:
0.000796
AC:
121
AN:
152100
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.00264
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00132
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000737
AC:
185
AN:
250858
Hom.:
0
AF XY:
0.000745
AC XY:
101
AN XY:
135584
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.0000994
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00213
Gnomad NFE exome
AF:
0.00118
Gnomad OTH exome
AF:
0.000655
GnomAD4 exome
AF:
0.000530
AC:
774
AN:
1461730
Hom.:
0
Cov.:
33
AF XY:
0.000560
AC XY:
407
AN XY:
727176
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00170
Gnomad4 NFE exome
AF:
0.000589
Gnomad4 OTH exome
AF:
0.000431
GnomAD4 genome
AF:
0.000795
AC:
121
AN:
152218
Hom.:
0
Cov.:
32
AF XY:
0.000968
AC XY:
72
AN XY:
74412
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00264
Gnomad4 NFE
AF:
0.00132
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.00107
Hom.:
0
Bravo
AF:
0.000351
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000774
AC:
94
EpiCase
AF:
0.000818
EpiControl
AF:
0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:7Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:1
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2022PDGFRA: BS1, BS2 -
Uncertain significance, no assertion criteria providedresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJul 13, 2012- -
Uncertain significance, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Gastrointestinal stromal tumor Benign:2
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 04, 2025- -
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 20, 2024This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submittercurationSema4, Sema4Feb 08, 2021- -
Idiopathic hypereosinophilic syndrome Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
PDGFRA-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 20, 2020This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not specified Other:1
not provided, no classification providedreference populationITMISep 19, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.64
T
BayesDel_noAF
Benign
-0.70
CADD
Benign
15
DANN
Benign
0.82
DEOGEN2
Benign
0.026
T;.
Eigen
Benign
-0.62
Eigen_PC
Benign
-0.44
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.51
T;T
M_CAP
Benign
0.0030
T
MetaRNN
Benign
0.0084
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N;N
PrimateAI
Benign
0.43
T
PROVEAN
Benign
1.4
N;N
REVEL
Benign
0.094
Sift
Benign
1.0
T;T
Sift4G
Benign
1.0
T;T
Polyphen
0.0
B;B
Vest4
0.089
MutPred
0.52
Loss of methylation at K197 (P = 0.1394);Loss of methylation at K197 (P = 0.1394);
MVP
0.38
MPC
0.29
ClinPred
0.041
T
GERP RS
4.8
Varity_R
0.13
gMVP
0.58

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: rs149951350; hg19: chr4-55130065; API