4-54274603-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_006206.6(PDGFRA):c.1631T>C(p.Val544Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000843 in 1,613,374 control chromosomes in the GnomAD database, including 3 homozygotes. 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. V544G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000079 ( 2 hom. )

Consequence

PDGFRA
NM_006206.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:4O:1

Conservation

PhyloP100: 7.28

Publications

12 publications found

Variant links:

COSMIC-nc: COSV109407087

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)

PDGFRA links:

ENSG00000282278 (HGNC:):

ENSG00000282278 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08857739).

BP6

Variant 4-54274603-T-C is Benign according to our data. Variant chr4-54274603-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 39617.

BS2

High AC in GnomAd4 at 20 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006206.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PDGFRA	NM_006206.6	MANE Select	c.1631T>C	p.Val544Ala	missense	Exon 11 of 23	NP_006197.1
PDGFRA	NM_001347828.2		c.1706T>C	p.Val569Ala	missense	Exon 12 of 24	NP_001334757.1
PDGFRA	NM_001347830.2		c.1670T>C	p.Val557Ala	missense	Exon 11 of 23	NP_001334759.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PDGFRA	ENST00000257290.10	TSL:1 MANE Select	c.1631T>C	p.Val544Ala	missense	Exon 11 of 23	ENSP00000257290.5
PDGFRA	ENST00000509092.5	TSL:1	n.1449T>C		non_coding_transcript_exon	Exon 10 of 15
PDGFRA	ENST00000509490.5	TSL:1	n.1631T>C		non_coding_transcript_exon	Exon 11 of 18	ENSP00000424218.1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000115

AC:

AN:

251290

AF XY:

0.000133

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00125

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.0000794

AC:

116

AN:

1461030

Hom.:

Cov.:

AF XY:

0.0000757

AC XY:

AN XY:

726942

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33468

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000781

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111242

Other (OTH)

AF:

0.00129

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000131

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41580

American (AMR)

AF:

0.000327

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00231

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000264

Hom.:

Bravo

AF:

0.000140

ExAC

AF:

0.000123

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:2

Dec 05, 2024

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Jul 31, 2020

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

Ovarian cancer

Pathogenic:1

Jan 01, 2022

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Significance:Likely pathogenic

Review Status:flagged submission

Collection Method:clinical testing

Idiopathic hypereosinophilic syndrome

Uncertain:1

Apr 12, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Isolated cleft palate

Uncertain:1

Oct 01, 2012

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

PDGFRA-related disorder

Benign:1

May 23, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Gastrointestinal stromal tumor

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.76

M_CAP

Benign

0.025

MetaRNN

Benign

0.089

MetaSVM

Uncertain

0.034

MutationAssessor

Pathogenic

3.1

PhyloP100

7.3

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.55

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

0.88

Vest4

0.63

MVP

0.77

MPC

0.62

ClinPred

0.22

GERP RS

5.9

Varity_R

0.28

gMVP

0.82

Mutation Taster

=21/79

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over