rs4358459

chr4-54267559-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006206.6(PDGFRA):c.939T>G(p.Gly313=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,613,524 control chromosomes in the GnomAD database, including 20,756 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2940 hom., cov: 32)
  • Exomes 𝑓: 0.14 (17816 hom.)
• Consequence: PDGFRA NM_006206.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.23

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-54267559-T-G is Benign according to our data. Variant chr4-54267559-T-G is described in ClinVar as [Benign]. Clinvar id is 259956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDGFRA	NM_006206.6	c.939T>G	p.Gly313=	synonymous_variant	7/23	ENST00000257290.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDGFRA	ENST00000257290.10	c.939T>G	p.Gly313=	synonymous_variant	7/23	1	NM_006206.6	P1
PDGFRA	ENST00000509092.5	n.757T>G		non_coding_transcript_exon_variant	6/15	1
PDGFRA	ENST00000509490.5	c.939T>G	p.Gly313=	synonymous_variant, NMD_transcript_variant	7/18	1

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27172 AN: 151930 Hom.: 2937 Cov.: 32

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.0651

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.247

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.149

GnomAD3 exomes AF: 0.185 AC: 46414 AN: 251130 Hom.: 5849 AF XY: 0.175 AC XY: 23786 AN XY: 135704

Gnomad AFR exome AF: 0.257

Gnomad AMR exome AF: 0.411

Gnomad ASJ exome AF: 0.0665

Gnomad EAS exome AF: 0.179

Gnomad SAS exome AF: 0.224

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.120

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.143 AC: 209339 AN: 1461476 Hom.: 17816 Cov.: 34 AF XY: 0.143 AC XY: 103815 AN XY: 727070

Gnomad4 AFR exome AF: 0.251

Gnomad4 AMR exome AF: 0.395

Gnomad4 ASJ exome AF: 0.0722

Gnomad4 EAS exome AF: 0.167

Gnomad4 SAS exome AF: 0.220

Gnomad4 FIN exome AF: 0.121

Gnomad4 NFE exome AF: 0.126

Gnomad4 OTH exome AF: 0.145

GnomAD4 genome AF: 0.179 AC: 27209 AN: 152048 Hom.: 2940 Cov.: 32 AF XY: 0.181 AC XY: 13488 AN XY: 74332

Gnomad4 AFR AF: 0.252

Gnomad4 AMR AF: 0.284

Gnomad4 ASJ AF: 0.0651

Gnomad4 EAS AF: 0.183

Gnomad4 SAS AF: 0.247

Gnomad4 FIN AF: 0.125

Gnomad4 NFE AF: 0.122

Gnomad4 OTH AF: 0.148

Alfa AF: 0.133 Hom.: 3015

Bravo AF: 0.193

Asia WGS AF: 0.247 AC: 859 AN: 3478

EpiCase AF: 0.113

EpiControl AF: 0.112

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gastrointestinal stromal tumor Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Idiopathic hypereosinophilic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2018

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	3.0
Dann	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs4358459; hg19: chr4-55133726; COSMIC: COSV57264201; COSMIC: COSV57264201;