rs1553903217

Variant names:

• chr4-54267336-C-G
• rs1553903217
• NM_006206.6:c.807C>G

Your query was ambiguous. Multiple possible variants found:

• chr4-54267336-C-G
• chr4-54267336-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_006206.6(PDGFRA):​c.807C>G​(p.Ile269Met) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I269V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDGFRA NM_006206.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19795132).
• BP6: Variant 4-54267336-C-G is Benign according to our data. Variant chr4-54267336-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3225318.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDGFRA	NM_006206.6	c.807C>G	p.Ile269Met	missense_variant	Exon 6 of 23	ENST00000257290.10	NP_006197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDGFRA	ENST00000257290.10	c.807C>G	p.Ile269Met	missense_variant	Exon 6 of 23	1	NM_006206.6	ENSP00000257290.5
PDGFRA	ENST00000509092.5	n.625C>G		non_coding_transcript_exon_variant	Exon 5 of 15	1
PDGFRA	ENST00000509490.5	n.807C>G		non_coding_transcript_exon_variant	Exon 6 of 18	1		ENSP00000424218.1
ENSG00000282278	ENST00000507166.5	c.1018-7589C>G		intron_variant	Intron 12 of 23	2		ENSP00000423325.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I269M variant (also known as c.807C>G), located in coding exon 5 of the PDGFRA gene, results from a C to G substitution at nucleotide position 807. The isoleucine at codon 269 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.87
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.1
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.085
Sift	Benign	0.35	T
Sift4G	Benign	0.28	T
Polyphen		0.055	B
Vest4		0.27
MutPred		0.45		Loss of methylation at K270 (P = 0.0788);
MVP		0.48
MPC		0.34
ClinPred		0.085	T
GERP RS		3.9
Varity_R		0.053
gMVP		0.63
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1553903217; hg19: chr4-55133503;