rs397514550

chr4-54295157-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_006206.6(PDGFRA):c.3155C>T(p.Thr1052Met) variant causes a missense change. The variant allele was found at a frequency of 0.000195 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. T1052S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: PDGFRA NM_006206.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1 O:1
• Conservation: PhyloP100: 5.85

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 Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PDGFRA
• BP4: Computational evidence support a benign effect (MetaRNN=0.03180799).
• BS2: High AC in GnomAd at 52 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDGFRA	NM_006206.6	c.3155C>T	p.Thr1052Met	missense_variant	23/23	ENST00000257290.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDGFRA	ENST00000257290.10	c.3155C>T	p.Thr1052Met	missense_variant	23/23	1	NM_006206.6	P1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152134 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00183

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: 0.000206

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000179 AC: 45 AN: 251234 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135774

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000179 AC: 262 AN: 1461766 Hom.: 0 Cov.: 35 AF XY: 0.000173 AC XY: 126 AN XY: 727194

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000207

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152252 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74440

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000230 Hom.: 0

Bravo AF: 0.000363

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Polyps, multiple and recurrent inflammatory fibroid, gastrointestinal Uncertain:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Likely benign and reported on 10-21-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Oct 06, 2022	The PDGFRA c.3155C>T (p.Thr1052Met) missense change has a maximum frequency of 0.051% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with PDGFRA-related conditions. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 14, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22473090, 30262796, 28873162, 32859249) -

Isolated cleft palate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Oct 01, 2012

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2020

The p.T1052M variant (also known as c.3155C>T), located in coding exon 22 of the PDGFRA gene, results from a C to T substitution at nucleotide position 3155. The threonine at codon 1052 is replaced by methionine, an amino acid with similar properties. This alteration was identified via multigene panel testing in a Mexican cohort suspicious for hereditary breast and/or ovarian cancer (Quezada U et al. Cancers (Basel) 2018 Sep;10(10)). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Gastrointestinal stromal tumor Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.15
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.032	T;T
MetaSVM	Uncertain	0.048	D
MutationTaster	Benign	0.76	N;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.076	T;T
Polyphen		1.0	.;D
Vest4		0.44
MVP		0.47
MPC		0.25
ClinPred		0.11	T
GERP RS		4.9
Varity_R		0.091
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs397514550; hg19: chr4-55161324; COSMIC: COSV57265542;