rs587778603

Positions:

• chr4-54272513-A-G
• chr4-54272513-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_006206.6(PDGFRA):​c.1357A>G​(p.Ile453Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,668 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I453F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: PDGFRA NM_006206.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 6.03

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 Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PDGFRA
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDGFRA	NM_006206.6	c.1357A>G	p.Ile453Val	missense_variant	9/23	ENST00000257290.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDGFRA	ENST00000257290.10	c.1357A>G	p.Ile453Val	missense_variant	9/23	1	NM_006206.6	P1
PDGFRA	ENST00000509092.5	n.1175A>G		non_coding_transcript_exon_variant	8/15	1
PDGFRA	ENST00000509490.5	c.1357A>G	p.Ile453Val	missense_variant, NMD_transcript_variant	9/18	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461668 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727140

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000117

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polyps, multiple and recurrent inflammatory fibroid, gastrointestinal Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

May 02, 2023

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 20, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In 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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 453 of the PDGFRA protein (p.Ile453Val). 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: 407443). 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) performed at Invitae indicates that this missense variant is not expected to disrupt PDGFRA protein function with a negative predictive value of 80%. 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 submitter

clinical testing

Ambry Genetics

Oct 13, 2023

The p.I453V variant (also known as c.1357A>G), located in coding exon 8 of the PDGFRA gene, results from an A to G substitution at nucleotide position 1357. The isoleucine at codon 453 is replaced by valine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. 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	Benign	0.12
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.042	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.15	N
REVEL	Uncertain	0.29
Sift	Benign	0.17	T
Sift4G	Benign	0.52	T
Polyphen		0.74	P
Vest4		0.57
MutPred		0.36		Gain of ubiquitination at K454 (P = 0.135);
MVP		0.74
MPC		0.28
ClinPred		0.66	D
GERP RS		6.2
Varity_R		0.14
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs587778603; hg19: chr4-55138680;