rs150577828

Positions:

• chr4-54272441-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_006206.6(PDGFRA):​c.1285G>A​(p.Gly429Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000436 in 1,613,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00045 (0 hom.)
• Consequence: PDGFRA NM_006206.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6
• Conservation: PhyloP100: 2.15

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 Benign. Variant got -8 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PDGFRA. . Gene score misZ 1.9401 (greater than the threshold 3.09). Trascript score misZ 3.4078 (greater than threshold 3.09). GenCC has associacion of gene with congenital heart disease, polyps, multiple and recurrent inflammatory fibroid, gastrointestinal, gastrointestinal stromal tumor, isolated cleft palate.
• BP4: Computational evidence support a benign effect (MetaRNN=0.06790626).
• BP6: Variant 4-54272441-G-A is Benign according to our data. Variant chr4-54272441-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41792.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=3}. Variant chr4-54272441-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDGFRA	NM_006206.6	c.1285G>A	p.Gly429Arg	missense_variant	9/23	ENST00000257290.10	NP_006197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDGFRA	ENST00000257290.10	c.1285G>A	p.Gly429Arg	missense_variant	9/23	1	NM_006206.6	ENSP00000257290.5
ENSG00000282278	ENST00000507166.5	c.1018-2484G>A		intron_variant		2		ENSP00000423325.1
PDGFRA	ENST00000509092.5	n.1103G>A		non_coding_transcript_exon_variant	8/15	1
PDGFRA	ENST00000509490.5	n.1285G>A		non_coding_transcript_exon_variant	9/18	1		ENSP00000424218.1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152068 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000370 AC: 93 AN: 251306 Hom.: 0 AF XY: 0.000405 AC XY: 55 AN XY: 135810

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000775

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000447 AC: 653 AN: 1461662 Hom.: 0 Cov.: 32 AF XY: 0.000432 AC XY: 314 AN XY: 727152

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000554

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152186 Hom.: 0 Cov.: 31 AF XY: 0.000336 AC XY: 25 AN XY: 74400

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000649 Hom.: 0

Bravo AF: 0.000378

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000478 AC: 58

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with malignant pleural mesothelioma (Bueno 2016); This variant is associated with the following publications: (PMID: 22703879, 26928227, 20071345) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PDGFRA: BP4, BS2 -

Gastrointestinal stromal tumor Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 20, 2024	This alteration is classified as 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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 09, 2020	- -

PDGFRA-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 12, 2024

The PDGFRA c.1285G>A variant is predicted to result in the amino acid substitution p.Gly429Arg. This variant has been reported in an individual with malignant pleural mesothelioma (Bueno et al. 2016. PubMed ID: 26928227, Table S5). It was identified in a ClinSeq participant and interpreted as uncertain significance (Johnson et al. 2012. PubMed ID: 22703879). It has also been reported in two unrelated individuals with a congenital heart defect, along with an unaffected parent (Bleyl et al. 2010. PubMed ID: 20071345). It is reported in 0.071% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/41792/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Idiopathic hypereosinophilic syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.5	L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.17
Sift	Benign	0.12	T
Sift4G	Benign	0.42	T
Polyphen		0.32	B
Vest4		0.44
MutPred		0.23		Gain of methylation at G429 (P = 0.0372);
MVP		0.57
MPC		0.39
ClinPred		0.038	T
GERP RS		3.5
Varity_R		0.070
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs150577828; hg19: chr4-55138608;