4-54285937-G-T

Position:

• chr4-54285937-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_006206.6(PDGFRA):​c.2536G>T​(p.Asp846Tyr) variant causes a missense change involving the alteration of a 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PDGFRA NM_006206.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 10.0

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 4-54285937-G-T is Pathogenic according to our data. Variant chr4-54285937-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13551.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDGFRA	NM_006206.6	c.2536G>T	p.Asp846Tyr	missense_variant	18/23	ENST00000257290.10	NP_006197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDGFRA	ENST00000257290.10	c.2536G>T	p.Asp846Tyr	missense_variant	18/23	1	NM_006206.6	ENSP00000257290.5
ENSG00000282278	ENST00000507166.5	c.1816G>T	p.Asp606Tyr	missense_variant	19/24	2		ENSP00000423325.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Polyps, multiple and recurrent inflammatory fibroid, gastrointestinal Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2004

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2024

The p.D846Y variant (also known as c.2536G>T), located in coding exon 17 of the PDGFRA gene, results from a G to T substitution at nucleotide position 2536. The aspartic acid at codon 846 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant was identified in one or more individuals with features consistent with PDGFRA-associated disease and segregated with disease in at least one family (external communication; Chompret A et al. Gastroenterology, 2004 Jan;126:318-21). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Gastrointestinal stromal tumor Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 19, 2018

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. This variant has been observed to segregate with gastrointestinal stromal tumor in a family (PMID: 14699510). ClinVar contains an entry for this variant (Variation ID: 13551). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with tyrosine at codon 846 of the PDGFRA protein (p.Asp846Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. Experimental studies have shown that this missense change does not confer resistance to kinase inhibitors in comparison with wild-type PDGFRA protein (PMID: 22745105). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	.;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	1.4	.;L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.0	D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		1.0	.;D
Vest4		0.97
MutPred		0.89		.;Loss of catalytic residue at D846 (P = 0.027);
MVP		0.95
MPC		1.2
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.91
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908588; hg19: chr4-55152104; COSMIC: COSV57265081; COSMIC: COSV57265081;