rs1553905281

chr4-54280335-G-Cchr4-54280335-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_006206.6(PDGFRA):c.2176G>C(p.Glu726Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E726E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PDGFRA NM_006206.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PDGFRA
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.811

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDGFRA	NM_006206.6	c.2176G>C	p.Glu726Gln	missense_variant	16/23	ENST00000257290.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDGFRA	ENST00000257290.10	c.2176G>C	p.Glu726Gln	missense_variant	16/23	1	NM_006206.6	P1
PDGFRA	ENST00000507536.1	n.602G>C		non_coding_transcript_exon_variant	4/5	1
PDGFRA	ENST00000509092.5	n.1994G>C		non_coding_transcript_exon_variant	15/15	1
PDGFRA	ENST00000509490.5	c.*97G>C		3_prime_UTR_variant, NMD_transcript_variant	17/18	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gastrointestinal stromal tumor Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 22, 2023

This variant is not present in population databases (gnomAD no frequency). 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. 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. ClinVar contains an entry for this variant (Variation ID: 528507). This variant has not been reported in the literature in individuals affected with PDGFRA-related conditions. This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 726 of the PDGFRA protein (p.Glu726Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	-0.044	T
MutationTaster	Benign	0.85	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Uncertain	0.58
Sift	Uncertain	0.028	D;D
Sift4G	Benign	0.087	T;D
Polyphen		1.0	.;D
Vest4		0.72
MutPred		0.60		.;Loss of sheet (P = 0.0315);
MVP		0.85
MPC		1.1
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.25
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs1553905281; hg19: chr4-55146502; COSMIC: COSV57266216; COSMIC: COSV57266216;