4-54277410-G-A

Position:

• chr4-54277410-G-A

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.1809G>A​(p.Ala603Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,612,388 control chromosomes in the GnomAD database, including 16,013 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (3008 hom., cov: 31)
  • Exomes 𝑓: 0.12 (13005 hom.)
• Consequence: PDGFRA NM_006206.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -5.22

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]

ENSG00000282278 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 4-54277410-G-A is Benign according to our data. Variant chr4-54277410-G-A is described in ClinVar as [Benign]. Clinvar id is 259950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.22 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDGFRA	NM_006206.6	c.1809G>A	p.Ala603Ala	synonymous_variant	13/23	ENST00000257290.10	NP_006197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDGFRA	ENST00000257290.10	c.1809G>A	p.Ala603Ala	synonymous_variant	13/23	1	NM_006206.6	ENSP00000257290.5
ENSG00000282278	ENST00000507166.5	c.1089G>A	p.Ala363Ala	synonymous_variant	14/24	2		ENSP00000423325.1

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26546 AN: 151862 Hom.: 3009 Cov.: 31

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.0545

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.145

GnomAD3 exomes AF: 0.159 AC: 40099 AN: 251462 Hom.: 4172 AF XY: 0.153 AC XY: 20793 AN XY: 135906

Gnomad AFR exome AF: 0.312

Gnomad AMR exome AF: 0.302

Gnomad ASJ exome AF: 0.0583

Gnomad EAS exome AF: 0.145

Gnomad SAS exome AF: 0.212

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.121 AC: 176694 AN: 1460408 Hom.: 13005 Cov.: 31 AF XY: 0.121 AC XY: 88234 AN XY: 726574

Gnomad4 AFR exome AF: 0.308

Gnomad4 AMR exome AF: 0.290

Gnomad4 ASJ exome AF: 0.0633

Gnomad4 EAS exome AF: 0.144

Gnomad4 SAS exome AF: 0.208

Gnomad4 FIN exome AF: 0.109

Gnomad4 NFE exome AF: 0.103

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.175 AC: 26560 AN: 151980 Hom.: 3008 Cov.: 31 AF XY: 0.177 AC XY: 13117 AN XY: 74274

Gnomad4 AFR AF: 0.305

Gnomad4 AMR AF: 0.215

Gnomad4 ASJ AF: 0.0545

Gnomad4 EAS AF: 0.145

Gnomad4 SAS AF: 0.232

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.143

Alfa AF: 0.131 Hom.: 727

Bravo AF: 0.187

Asia WGS AF: 0.200 AC: 696 AN: 3478

EpiCase AF: 0.0973

EpiControl AF: 0.0957

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	Labcorp Genetics (formerly Invitae), Labcorp	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. -

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	-0.80
CADD	Benign	1.1
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: rs10028020; hg19: chr4-55143577; COSMIC: COSV57265177;