rs149031291

chr4-54273622-G-Achr4-54273622-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_006206.6(PDGFRA):c.1450G>A(p.Val484Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000768 in 1,613,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign 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. V484L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: PDGFRA NM_006206.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 3.18

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PDGFRA
• BP4: Computational evidence support a benign effect (MetaRNN=0.20390713).
• BP6: Variant 4-54273622-G-A is Benign according to our data. Variant chr4-54273622-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 240309.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=1, Benign=1}.
• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDGFRA	NM_006206.6	c.1450G>A	p.Val484Met	missense_variant	10/23	ENST00000257290.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDGFRA	ENST00000257290.10	c.1450G>A	p.Val484Met	missense_variant	10/23	1	NM_006206.6	P1
PDGFRA	ENST00000509092.5	n.1268G>A		non_coding_transcript_exon_variant	9/15	1
PDGFRA	ENST00000509490.5	c.1450G>A	p.Val484Met	missense_variant, NMD_transcript_variant	10/18	1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152096 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251124 Hom.: 0 AF XY: 0.0000884 AC XY: 12 AN XY: 135706

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000800 AC: 117 AN: 1461780 Hom.: 0 Cov.: 33 AF XY: 0.0000866 AC XY: 63 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000899

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152096 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74296

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000604

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest no impact on protein function (Ip et al., 2018); This variant is associated with the following publications: (PMID: 30389923) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 28, 2018	- -

Gastrointestinal stromal tumor Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 19, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 484 of the PDGFRA protein (p.Val484Met). This variant is present in population databases (rs149031291, gnomAD 0.02%). 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: 240309). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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 does not substantially affect PDGFRA function (PMID: 30389923). 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. -

Idiopathic hypereosinophilic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 15, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

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	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.66	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.21
Sift	Benign	0.054	T
Sift4G	Benign	0.12	T
Polyphen		0.53	P
Vest4		0.32
MVP		0.75
MPC		0.33
ClinPred		0.14	T
GERP RS		2.8
Varity_R		0.046
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149031291; hg19: chr4-55139789;