4-54270633-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006206.6(PDGFRA):c.1122G>C(p.Arg374Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000311 in 1,564,740 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R374R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

PDGFRA
NM_006206.6 missense, splice_region

Scores

Splicing: ADA: 0.2050

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 0.231

Publications

6 publications found

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 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008614212).

BP6

Variant 4-54270633-G-C is Benign according to our data. Variant chr4-54270633-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 265 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDGFRA	NM_006206.6 link	c.1122G>C	p.Arg374Ser	missense_variant, splice_region_variant	Exon 8 of 23	ENST00000257290.10	NP_006197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PDGFRA	ENST00000257290.10 link	c.1122G>C	p.Arg374Ser	missense_variant, splice_region_variant	Exon 8 of 23	1	NM_006206.6	ENSP00000257290.5
PDGFRA	ENST00000509092.5 link	n.940G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 7 of 15	1
PDGFRA	ENST00000509490.5 link	n.1122G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 18	1		ENSP00000424218.1
ENSG00000282278	ENST00000507166.5 link	c.1018-4292G>C		intron_variant	Intron 12 of 23	2		ENSP00000423325.1

Frequencies

GnomAD3 genomes

AF:

0.00174

AC:

265

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00626

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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

GnomAD2 exomes

AF:

0.000443

AC:

111

AN:

250816

AF XY:

0.000288

show subpopulations

Gnomad AFR exome

AF:

0.00628

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000156

AC:

221

AN:

1412574

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

706084

show subpopulations

African (AFR)

AF:

0.00576

AC:

187

AN:

32488

American (AMR)

AF:

0.000246

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25792

East Asian (EAS)

AF:

0.00

AC:

AN:

39444

South Asian (SAS)

AF:

0.00

AC:

AN:

85248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52882

Middle Eastern (MID)

AF:

0.000177

AC:

AN:

5646

European-Non Finnish (NFE)

AF:

0.00000187

AC:

AN:

1067576

Other (OTH)

AF:

0.000340

AC:

AN:

58816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.00174

AC:

265

AN:

152166

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

124

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.00624

AC:

259

AN:

41502

American (AMR)

AF:

0.000327

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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:

0.000424

Hom.:

Bravo

AF:

0.00200

ESP6500AA

AF:

0.00635

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000552

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Gastrointestinal stromal tumor

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Benign:2

May 30, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

Dec 05, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Idiopathic hypereosinophilic syndrome

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

PDGFRA-related disorder

Benign:1

Dec 30, 2021

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).

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Uncertain

0.49

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.70

MetaRNN

Benign

0.0086

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

0.23

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.029

Sift

Benign

0.22

Sift4G

Benign

0.31

Vest4

0.18

ClinPred

0.014

GERP RS

2.2

Varity_R

0.25

gMVP

0.67

Mutation Taster

=58/42

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.20

dbscSNV1_RF

Benign

0.38

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over