chr4-54290376-G-A

Position:

• chr4-54290376-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_006206.6(PDGFRA):​c.2944G>A​(p.Val982Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V982A) 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: 2.73

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.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PDGFRA. . Gene score misZ 1.9401 (greater than the threshold 3.09). Trascript score misZ 3.4078 (greater than threshold 3.09). GenCC has associacion of gene with congenital heart disease, polyps, multiple and recurrent inflammatory fibroid, gastrointestinal, gastrointestinal stromal tumor, isolated cleft palate.
• BP4: Computational evidence support a benign effect (MetaRNN=0.16072711).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDGFRA	NM_006206.6	c.2944G>A	p.Val982Met	missense_variant	22/23	ENST00000257290.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDGFRA	ENST00000257290.10	c.2944G>A	p.Val982Met	missense_variant	22/23	1	NM_006206.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Sep 29, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with PDGFRA-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with methionine at codon 982 of the PDGFRA protein (p.Val982Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.036	.;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.030
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.90	.;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.31	N;N
REVEL	Benign	0.18
Sift	Benign	0.15	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.031	.;B
Vest4		0.26
MutPred		0.32		.;Gain of disorder (P = 0.0828);
MVP		0.32
MPC		0.033
ClinPred		0.34	T
GERP RS		5.8
Varity_R		0.086
gMVP		0.41

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: rs1553906630; hg19: chr4-55156543; COSMIC: COSV99955520;