rs552254049

chr4-54290412-A-Gchr4-54290412-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_006206.6(PDGFRA):c.2980A>G(p.Lys994Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,072 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. K994R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PDGFRA NM_006206.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.84

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 1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PDGFRA

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDGFRA	NM_006206.6	c.2980A>G	p.Lys994Glu	missense_variant	22/23	ENST00000257290.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDGFRA	ENST00000257290.10	c.2980A>G	p.Lys994Glu	missense_variant	22/23	1	NM_006206.6	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461722 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74512

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gastrointestinal stromal tumor Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 25, 2022

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 994 of the PDGFRA protein (p.Lys994Glu). 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: 459078). 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. 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 27, 2023

The p.K994E variant (also known as c.2980A>G), located in coding exon 21 of the PDGFRA gene, results from an A to G substitution at nucleotide position 2980. The lysine at codon 994 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. 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	0.15
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Uncertain	-0.13	T
MutationTaster	Benign	0.89	N;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.77	N;N
REVEL	Uncertain	0.40
Sift	Benign	0.17	T;T
Sift4G	Benign	0.83	T;T
Polyphen		1.0	.;D
Vest4		0.72
MutPred		0.42		.;Loss of ubiquitination at K994 (P = 0.0039);
MVP		0.77
MPC		0.27
ClinPred		0.73	D
GERP RS		5.8
Varity_R		0.27
gMVP		0.78

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

Other links and lift over

dbSNP: rs552254049; hg19: chr4-55156579;