rs760631068

Variant summary

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

The NM_006206.6(PDGFRA):​c.466G>A​(p.Glu156Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000818 in 1,613,938 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000077 ( 1 hom. )

Consequence

PDGFRA
NM_006206.6 missense

Scores

19

Clinical Significance

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

Conservation

PhyloP100: -0.168
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=0.014832288).
BP6
Variant 4-54263765-G-A is Benign according to our data. Variant chr4-54263765-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 407397.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1, Benign=1}.
BS2
High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PDGFRANM_006206.6 linkc.466G>A p.Glu156Lys 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.466G>A p.Glu156Lys missense_variant 4/231 NM_006206.6 ENSP00000257290.5 P16234-1
ENSG00000282278ENST00000507166.5 linkc.1018-11160G>A intron_variant 2 ENSP00000423325.1 A0A0B4J203

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
152096
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00105
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000195
AC:
49
AN:
251276
Hom.:
0
AF XY:
0.000206
AC XY:
28
AN XY:
135788
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000521
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000784
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000773
AC:
113
AN:
1461842
Hom.:
1
Cov.:
33
AF XY:
0.0000921
AC XY:
67
AN XY:
727230
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000582
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000754
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.000125
AC:
19
AN:
152096
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
AN XY:
74284
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00105
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000204
Hom.:
0
Bravo
AF:
0.000355
ExAC
AF:
0.000222
AC:
27
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000178

ClinVar

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

Submissions by phenotype

PDGFRA-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 08, 2024The PDGFRA c.466G>A variant is predicted to result in the amino acid substitution p.Glu156Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.078% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as uncertain or likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/407397/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxSep 22, 2022In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Gastrointestinal stromal tumor Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 17, 2024- -
Hereditary cancer-predisposing syndrome Benign:1
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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.064
BayesDel_addAF
Benign
-0.58
T
BayesDel_noAF
Benign
-0.69
CADD
Benign
11
DANN
Benign
0.79
DEOGEN2
Benign
0.047
T;.;.;.
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.030
N
LIST_S2
Benign
0.74
T;T;T;T
M_CAP
Benign
0.0087
T
MetaRNN
Benign
0.015
T;T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
1.4
L;L;.;.
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-0.63
N;N;N;N
REVEL
Benign
0.019
Sift
Benign
0.79
T;T;T;T
Sift4G
Benign
0.69
T;T;T;T
Polyphen
0.0010
B;B;.;.
Vest4
0.085
MutPred
0.39
Gain of methylation at E156 (P = 0.0108);Gain of methylation at E156 (P = 0.0108);Gain of methylation at E156 (P = 0.0108);Gain of methylation at E156 (P = 0.0108);
MVP
0.23
MPC
0.36
ClinPred
0.013
T
GERP RS
-2.2
Varity_R
0.040
gMVP
0.60

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: rs760631068; hg19: chr4-55129932; COSMIC: COSV57266689; COSMIC: COSV57266689; API