4-54277974-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS2

The NM_006206.6(PDGFRA):c.1970T>C(p.Ile657Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. I657V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PDGFRA
NM_006206.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.95

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: Likely_benign. The variant received -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.928

BP6

Variant 4-54277974-T-C is Benign according to our data. Variant chr4-54277974-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 578636. Variant chr4-54277974-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 578636. Variant chr4-54277974-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 578636. Variant chr4-54277974-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 578636. Variant chr4-54277974-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 578636. Variant chr4-54277974-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 578636. Variant chr4-54277974-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 578636. Variant chr4-54277974-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 578636. Variant chr4-54277974-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 578636. Variant chr4-54277974-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 578636. Variant chr4-54277974-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 578636. Variant chr4-54277974-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 578636. Variant chr4-54277974-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 578636. Variant chr4-54277974-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 578636. Variant chr4-54277974-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 578636. Variant chr4-54277974-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 578636. Variant chr4-54277974-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 578636. Variant chr4-54277974-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 578636. Variant chr4-54277974-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 578636. Variant chr4-54277974-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 578636.

BS2

High AC in GnomAd4 at 5 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDGFRA	NM_006206.6 link	c.1970T>C	p.Ile657Thr	missense_variant	Exon 14 of 23	ENST00000257290.10	NP_006197.1	P16234-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDGFRA	ENST00000257290.10 link	c.1970T>C	p.Ile657Thr	missense_variant	Exon 14 of 23	1	NM_006206.6	ENSP00000257290.5		P16234-1
ENSG00000282278	ENST00000507166.5 link	c.1250T>C	p.Ile417Thr	missense_variant	Exon 15 of 24	2		ENSP00000423325.1		A0A0B4J203

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461054

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726908

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111246

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41404

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Idiopathic hypereosinophilic syndrome;C5193005:Polyps, multiple and recurrent inflammatory fibroid, gastrointestinal

Uncertain:1

Dec 08, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Gastrointestinal stromal tumor

Uncertain:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 657 of the PDGFRA protein (p.Ile657Thr). This variant is present in population databases (no rsID available, 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: 578636). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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

Benign:1

Oct 17, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

.;D

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.85

D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Uncertain

2.1

.;M

PhyloP100

7.9

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-4.2

D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.013

D;T

Polyphen

0.99

.;D

Vest4

0.94

MVP

0.98

MPC

1.2

ClinPred

0.99

GERP RS

5.8

Varity_R

0.82

gMVP

0.94

Mutation Taster

=36/64

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over