rs587778594

Variant names:

• chr4-54273589-A-G
• rs587778594
• NM_006206.6:c.1417A>G

Your query was ambiguous. Multiple possible variants found:

• chr4-54273589-A-G
• chr4-54273589-A-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006206.6(PDGFRA):​c.1417A>G​(p.Ile473Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PDGFRA NM_006206.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1 O:1
• Conservation: PhyloP100: 0.0850
• Publications: 3 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.040114045).
• BP6: Variant 4-54273589-A-G is Benign according to our data. Variant chr4-54273589-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135012.
• BS2: High AC in GnomAdExome4 at 7 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.1417A>G	p.Ile473Val	missense	Exon 10 of 23	NP_006197.1	P16234-1
	PDGFRA	NM_001347828.2		c.1492A>G	p.Ile498Val	missense	Exon 11 of 24	NP_001334757.1
	PDGFRA	NM_001347830.2		c.1456A>G	p.Ile486Val	missense	Exon 10 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.1417A>G	p.Ile473Val	missense	Exon 10 of 23	ENSP00000257290.5	P16234-1
	ENSG00000282278	ENST00000507166.5	TSL:2	c.1018-1336A>G		intron	N/A	ENSP00000423325.1	A0A0B4J203
	PDGFRA	ENST00000509092.5	TSL:1	n.1235A>G		non_coding_transcript_exon	Exon 9 of 15

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000468 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Gastrointestinal stromal tumor (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.014
DANN	Benign	0.26
DEOGEN2	Benign	0.037	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.085
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.42	N
REVEL	Benign	0.13
Sift	Benign	0.70	T
Sift4G	Benign	0.92	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.22		Gain of disorder (P = 0.1735)
MVP		0.30
MPC		0.27
ClinPred		0.050	T
GERP RS		-10
Varity_R		0.020
gMVP		0.37
Mutation Taster		=96/4	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: rs587778594; hg19: chr4-55139756;