4-54285398-A-G

Variant names:

• chr4-54285398-A-G
• rs900860957
• NM_006206.6:c.2351A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_006206.6(PDGFRA):​c.2351A>G​(p.Asp784Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000729 in 1,371,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. D784Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000073 (0 hom.)
• Consequence: PDGFRA NM_006206.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35
• 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: G2P, Ambry Genetics, Genomics England PanelApp
• 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_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 10 Unknown,AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDGFRA	NM_006206.6	MANE Select	c.2351A>G	p.Asp784Gly	missense	Exon 17 of 23	NP_006197.1	P16234-1
	PDGFRA	NM_001347828.2		c.2426A>G	p.Asp809Gly	missense	Exon 18 of 24	NP_001334757.1
	PDGFRA	NM_001347830.2		c.2390A>G	p.Asp797Gly	missense	Exon 17 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.2351A>G	p.Asp784Gly	missense	Exon 17 of 23	ENSP00000257290.5	P16234-1
	ENSG00000282278	ENST00000507166.5	TSL:2	c.1631A>G	p.Asp544Gly	missense	Exon 18 of 24	ENSP00000423325.1	A0A0B4J203
	PDGFRA	ENST00000870889.1		c.2351A>G	p.Asp784Gly	missense	Exon 17 of 23	ENSP00000540948.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000729 AC: 10 AN: 1371422 Hom.: 0 Cov.: 23 AF XY: 0.00000727 AC XY: 5 AN XY: 687578

African (AFR) AF: 0.00 AC: 0 AN: 31706

American (AMR) AF: 0.00 AC: 0 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25586

East Asian (EAS) AF: 0.000153 AC: 6 AN: 39294

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 0.00000291 AC: 3 AN: 1029428

Other (OTH) AF: 0.00 AC: 0 AN: 57374

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Gastrointestinal stromal tumor (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.77	N
PhyloP100		7.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.59
Sift	Benign	0.039	D
Sift4G	Benign	0.070	T
Polyphen		0.89	P
Vest4		0.40
MutPred		0.46		Loss of stability (P = 0.0166)
MVP		0.72
MPC		1.2
ClinPred		0.88	D
GERP RS		5.9
Varity_R		0.40
gMVP		0.62
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs900860957; hg19: chr4-55151565;