rs1178568199

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2

The NM_006206.6(PDGFRA):c.1352A>C(p.Lys451Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,613,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

PDGFRA
NM_006206.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.44

Variant links:

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 links:

ENSG00000282278 (HGNC:):

ENSG00000282278 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 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=0.38581905).

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDGFRA	NM_006206.6 linkuse as main transcript	c.1352A>C	p.Lys451Thr	missense_variant	9/23	ENST00000257290.10	NP_006197.1	P16234-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PDGFRA	ENST00000257290.10 linkuse as main transcript	c.1352A>C	p.Lys451Thr	missense_variant	9/23	1	NM_006206.6	ENSP00000257290.5	P16234-1
ENSG00000282278	ENST00000507166.5 linkuse as main transcript	c.1018-2417A>C		intron_variant		2		ENSP00000423325.1	A0A0B4J203
PDGFRA	ENST00000509092.5 linkuse as main transcript	n.1170A>C		non_coding_transcript_exon_variant	8/15	1
PDGFRA	ENST00000509490.5 linkuse as main transcript	n.1352A>C		non_coding_transcript_exon_variant	9/18	1		ENSP00000424218.1	P16234-3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461724

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PDGFRA-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 09, 2024

The PDGFRA c.1352A>C variant is predicted to result in the amino acid substitution p.Lys451Thr. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/653134/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Gastrointestinal stromal tumor

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 451 of the PDGFRA protein (p.Lys451Thr). This variant is not present in population databases (gnomAD no frequency). 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: 653134). 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%. 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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2023

The p.K451T variant (also known as c.1352A>C), located in coding exon 8 of the PDGFRA gene, results from an A to C substitution at nucleotide position 1352. The lysine at codon 451 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.031

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.083

Eigen

Benign

0.020

Eigen_PC

Benign

0.0042

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.045

MetaRNN

Benign

0.39

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.1

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.33

Sift

Benign

0.051

Sift4G

Benign

0.30

Polyphen

0.89

Vest4

0.41

MutPred

0.48

Loss of methylation at K451 (P = 2e-04);

MVP

0.73

MPC

0.40

ClinPred

0.56

GERP RS

2.5

Varity_R

0.11

gMVP

0.82

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over