chr4-54285850-C-G

Variant names:

• chr4-54285850-C-G
• rs776099721
• NM_006206.6:c.2449C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001347828.2(PDGFRA):​c.2524C>G​(p.Arg842Gly) variant causes a missense change. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R842C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PDGFRA NM_001347828.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.88
• Publications: 1 publications found

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]

PDGFRA Gene-Disease associations (from GenCC):

• gastrointestinal stromal tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• polyps, multiple and recurrent inflammatory fibroid, gastrointestinal

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• isolated cleft palate

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000282278 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347828.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDGFRA	NM_006206.6	MANE Select	c.2449C>G	p.Arg817Gly	missense	Exon 18 of 23	NP_006197.1
	PDGFRA	NM_001347828.2		c.2524C>G	p.Arg842Gly	missense	Exon 19 of 24	NP_001334757.1
	PDGFRA	NM_001347830.2		c.2488C>G	p.Arg830Gly	missense	Exon 18 of 23	NP_001334759.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDGFRA	ENST00000257290.10	TSL:1 MANE Select	c.2449C>G	p.Arg817Gly	missense	Exon 18 of 23	ENSP00000257290.5
	ENSG00000282278	ENST00000507166.5	TSL:2	c.1729C>G	p.Arg577Gly	missense	Exon 19 of 24	ENSP00000423325.1
	PDGFRA	ENST00000870889.1		c.2449C>G	p.Arg817Gly	missense	Exon 18 of 23	ENSP00000540948.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Gastrointestinal stromal tumor (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	0.95	L
PhyloP100		3.9
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.037	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.94		Gain of ubiquitination at K812 (P = 0.0741)
MVP		0.97
MPC		1.2
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.90
gMVP		0.94
Mutation Taster		=14/86	disease causing

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

Other links and lift over

dbSNP: rs776099721; hg19: chr4-55152017;