4-54289018-C-G

Variant names:

• chr4-54289018-C-G
• rs764838149
• NM_006206.6:c.2784C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006206.6(PDGFRA):​c.2784C>G​(p.Ile928Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,356 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PDGFRA NM_006206.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.823

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]

ENSG00000282278 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDGFRA	NM_006206.6	c.2784C>G	p.Ile928Met	missense_variant	Exon 21 of 23	ENST00000257290.10	NP_006197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDGFRA	ENST00000257290.10	c.2784C>G	p.Ile928Met	missense_variant	Exon 21 of 23	1	NM_006206.6	ENSP00000257290.5
ENSG00000282278	ENST00000507166.5	c.2064C>G	p.Ile688Met	missense_variant	Exon 22 of 24	2		ENSP00000423325.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251206 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455356 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 724460

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: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gastrointestinal stromal tumor Uncertain:1

Dec 18, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine with methionine at codon 928 of the PDGFRA protein (p.Ile928Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs764838149, ExAC 0.001%). This variant has not been reported in the literature in individuals with PDGFRA-related disease. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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

Jun 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I928M variant (also known as c.2784C>G), located in coding exon 20 of the PDGFRA gene, results from a C to G substitution at nucleotide position 2784. The isoleucine at codon 928 is replaced by methionine, 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	0.074
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.42	.;T
Eigen	Benign	-0.069
Eigen_PC	Benign	0.073
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Benign	1.3	.;L
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.58
Sift	Benign	0.049	D;T
Sift4G	Benign	0.45	T;T
Polyphen		0.087	.;B
Vest4		0.37
MutPred		0.67		.;Gain of disorder (P = 0.0398);
MVP		0.89
MPC		1.8
ClinPred		0.36	T
GERP RS		4.3
Varity_R		0.55
gMVP		0.68

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: rs764838149; hg19: chr4-55155185;