4-54285934-C-T

Variant names:

• chr4-54285934-C-T
• rs1057519814
• NM_006206.6:c.2533C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006206.6(PDGFRA):​c.2533C>T​(p.His845Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PDGFRA NM_006206.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.04

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]

ENSG00000282278 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDGFRA	NM_006206.6	c.2533C>T	p.His845Tyr	missense_variant	Exon 18 of 23	ENST00000257290.10	NP_006197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDGFRA	ENST00000257290.10	c.2533C>T	p.His845Tyr	missense_variant	Exon 18 of 23	1	NM_006206.6	ENSP00000257290.5
ENSG00000282278	ENST00000507166.5	c.1813C>T	p.His605Tyr	missense_variant	Exon 19 of 24	2		ENSP00000423325.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gastrointestinal stromal tumor Uncertain:1

Nov 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 845 of the PDGFRA protein (p.His845Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PDGFRA-related conditions. ClinVar contains an entry for this variant (Variation ID: 376184). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PDGFRA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PDGFRA function (PMID: 24132921). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	.;D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	0.59	.;N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.027	D;D
Sift4G	Benign	0.22	T;T
Polyphen		1.0	.;D
Vest4		0.65
MutPred		0.44		.;Loss of disorder (P = 0.0507);
MVP		0.76
MPC		1.1
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.46
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.60		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.60		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519814; hg19: chr4-55152101; COSMIC: COSV57272664; COSMIC: COSV57272664;