Genetic Variant PDGFRA:p.Ser776Ala (chr4-54285373-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001347828.2(PDGFRA):c.2401T>G(p.Ser801Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S801S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

PDGFRA
NM_001347828.2 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.618

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.054229498).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347828.2. 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.2326T>G	p.Ser776Ala	missense splice_region	Exon 17 of 23	NP_006197.1
PDGFRA	NM_001347828.2		c.2401T>G	p.Ser801Ala	missense splice_region	Exon 18 of 24	NP_001334757.1
PDGFRA	NM_001347830.2		c.2365T>G	p.Ser789Ala	missense splice_region	Exon 17 of 23	NP_001334759.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PDGFRA	ENST00000257290.10	TSL:1 MANE Select	c.2326T>G	p.Ser776Ala	missense splice_region	Exon 17 of 23	ENSP00000257290.5
ENSG00000282278	ENST00000507166.5	TSL:2	c.1606T>G	p.Ser536Ala	missense splice_region	Exon 18 of 24	ENSP00000423325.1
PDGFRA	ENST00000870889.1		c.2326T>G	p.Ser776Ala	missense splice_region	Exon 17 of 23	ENSP00000540948.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Gastrointestinal stromal tumor (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.17

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.43

M_CAP

Benign

0.043

MetaRNN

Benign

0.054

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.30

PhyloP100

0.62

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.38

REVEL

Benign

0.12

Sift

Benign

0.74

Sift4G

Benign

0.78

Polyphen

0.059

Vest4

0.17

MutPred

0.48

Loss of phosphorylation at S776 (P = 0.0287)

MVP

0.48

MPC

0.27

ClinPred

0.082

GERP RS

2.9

Varity_R

0.14

gMVP

0.26

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over