4-54285873-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_006206.6(PDGFRA):c.2472C>T(p.Val824=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,613,562 control chromosomes in the GnomAD database, including 23,115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V824V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.20 (3681 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19434 hom.)
• Consequence: PDGFRA NM_006206.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.640

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21).
• BP6: Variant 4-54285873-C-T is Benign according to our data. Variant chr4-54285873-C-T is described in ClinVar as [Benign]. Clinvar id is 259951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDGFRA	NM_006206.6	c.2472C>T	p.Val824=	synonymous_variant	18/23	ENST00000257290.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDGFRA	ENST00000257290.10	c.2472C>T	p.Val824=	synonymous_variant	18/23	1	NM_006206.6	P1

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30628 AN: 151998 Hom.: 3682 Cov.: 32

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.0683

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.168

GnomAD3 exomes AF: 0.183 AC: 46035 AN: 251358 Hom.: 5051 AF XY: 0.177 AC XY: 24023 AN XY: 135846

Gnomad AFR exome AF: 0.329

Gnomad AMR exome AF: 0.314

Gnomad ASJ exome AF: 0.0740

Gnomad EAS exome AF: 0.141

Gnomad SAS exome AF: 0.217

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.156 AC: 227945 AN: 1461444 Hom.: 19434 Cov.: 34 AF XY: 0.155 AC XY: 112889 AN XY: 727076

Gnomad4 AFR exome AF: 0.327

Gnomad4 AMR exome AF: 0.304

Gnomad4 ASJ exome AF: 0.0783

Gnomad4 EAS exome AF: 0.141

Gnomad4 SAS exome AF: 0.214

Gnomad4 FIN exome AF: 0.126

Gnomad4 NFE exome AF: 0.145

Gnomad4 OTH exome AF: 0.152

GnomAD4 genome AF: 0.201 AC: 30643 AN: 152118 Hom.: 3681 Cov.: 32 AF XY: 0.201 AC XY: 14956 AN XY: 74346

Gnomad4 AFR AF: 0.323

Gnomad4 AMR AF: 0.235

Gnomad4 ASJ AF: 0.0683

Gnomad4 EAS AF: 0.143

Gnomad4 SAS AF: 0.236

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.143

Gnomad4 OTH AF: 0.166

Alfa AF: 0.154 Hom.: 4733

Bravo AF: 0.215

Asia WGS AF: 0.211 AC: 732 AN: 3478

EpiCase AF: 0.135

EpiControl AF: 0.135

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Gastrointestinal stromal tumor Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Idiopathic hypereosinophilic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

May 08, 2019

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	-0.21
Cadd	Benign	8.1
Dann	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2228230; hg19: chr4-55152040; COSMIC: COSV57264143; COSMIC: COSV57264143;