4-54274600-T-C

Variant names:

• chr4-54274600-T-C
• rs755486487
• NM_006206.6:c.1628T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BP6 BS2

The NM_006206.6(PDGFRA):​c.1628T>C​(p.Ile543Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. I543M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PDGFRA NM_006206.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 7.28
• 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 -4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838
• BP6: Variant 4-54274600-T-C is Benign according to our data. Variant chr4-54274600-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 459013.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS2: High AC in GnomAdExome4 at 6 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDGFRA	NM_006206.6	c.1628T>C	p.Ile543Thr	missense_variant	Exon 11 of 23	ENST00000257290.10	NP_006197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDGFRA	ENST00000257290.10	c.1628T>C	p.Ile543Thr	missense_variant	Exon 11 of 23	1	NM_006206.6	ENSP00000257290.5
PDGFRA	ENST00000509092.5	n.1446T>C		non_coding_transcript_exon_variant	Exon 10 of 15	1
PDGFRA	ENST00000509490.5	n.1628T>C		non_coding_transcript_exon_variant	Exon 11 of 18	1		ENSP00000424218.1
ENSG00000282278	ENST00000507166.5	c.1018-325T>C		intron_variant	Intron 12 of 23	2		ENSP00000423325.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251280 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460986 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726908

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111198

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Idiopathic hypereosinophilic syndrome;C5193005:Polyps, multiple and recurrent inflammatory fibroid, gastrointestinal Uncertain:1

Feb 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gastrointestinal stromal tumor Uncertain:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 543 of the PDGFRA protein (p.Ile543Thr). This variant is present in population databases (rs755486487, gnomAD 0.01%). 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: 459013). 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%. 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. -

Hereditary cancer-predisposing syndrome Benign:1

Oct 02, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.45		Loss of stability (P = 0.0047);
MVP		0.84
MPC		1.2
ClinPred		0.86	D
GERP RS		4.7
Varity_R		0.41
gMVP		0.85
Mutation Taster		=28/72	disease causing

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

Other links and lift over

dbSNP: rs755486487; hg19: chr4-55140767;