chr4-54267406-C-A

Variant names:

• chr4-54267406-C-A
• rs762106764
• NM_006206.6:c.877C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006206.6(PDGFRA):​c.877C>A​(p.Arg293Ser) 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. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R293H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDGFRA NM_006206.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1279661).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006206.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDGFRA	NM_006206.6	MANE Select	c.877C>A	p.Arg293Ser	missense	Exon 6 of 23	NP_006197.1
	PDGFRA	NM_001347828.2		c.952C>A	p.Arg318Ser	missense	Exon 7 of 24	NP_001334757.1
	PDGFRA	NM_001347830.2		c.916C>A	p.Arg306Ser	missense	Exon 6 of 23	NP_001334759.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDGFRA	ENST00000257290.10	TSL:1 MANE Select	c.877C>A	p.Arg293Ser	missense	Exon 6 of 23	ENSP00000257290.5
	PDGFRA	ENST00000509092.5	TSL:1	n.695C>A		non_coding_transcript_exon	Exon 5 of 15
	PDGFRA	ENST00000509490.5	TSL:1	n.877C>A		non_coding_transcript_exon	Exon 6 of 18	ENSP00000424218.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.92	L
PhyloP100		1.0
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.11
Sift	Benign	0.63	T
Sift4G	Benign	0.75	T
Polyphen		0.021	B
Vest4		0.55
MutPred		0.40		Loss of MoRF binding (P = 0.0236)
MVP		0.44
MPC		0.40
ClinPred		0.25	T
GERP RS		3.9
Varity_R		0.31
gMVP		0.73
Mutation Taster		=91/9	polymorphism

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: rs762106764; hg19: chr4-55133573; COSMIC: COSV99957780; COSMIC: COSV99957780;