chr4-54277955-C-G

Variant names:

• chr4-54277955-C-G
• rs878854826
• NM_006206.6:c.1951C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006206.6(PDGFRA):​c.1951C>G​(p.Leu651Val) 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 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. L651P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PDGFRA NM_006206.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.74
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDGFRA	NM_006206.6	c.1951C>G	p.Leu651Val	missense_variant	Exon 14 of 23	ENST00000257290.10	NP_006197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDGFRA	ENST00000257290.10	c.1951C>G	p.Leu651Val	missense_variant	Exon 14 of 23	1	NM_006206.6	ENSP00000257290.5
ENSG00000282278	ENST00000507166.5	c.1231C>G	p.Leu411Val	missense_variant	Exon 15 of 24	2		ENSP00000423325.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 14, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	.;D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	1.3	.;L
PhyloP100		2.7
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.3	N;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.041	D;D
Polyphen		1.0	.;D
Vest4		0.70
MutPred		0.76		.;Loss of helix (P = 0.0444);
MVP		0.94
MPC		1.1
ClinPred		0.94	D
GERP RS		4.1
Varity_R		0.82
gMVP		0.81
Mutation Taster		=26/74	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: rs878854826; hg19: chr4-55144122;