4-54274918-G-A

Variant names:

• chr4-54274918-G-A
• rs55830582
• NM_006206.6:c.1731G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006206.6(PDGFRA):​c.1731G>A​(p.Pro577Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,614,090 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P577P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (48 hom.)
• Consequence: PDGFRA NM_006206.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:7
• Conservation: PhyloP100: -2.17
• Publications: 6 publications found

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)

ENSG00000282278 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-54274918-G-A is Benign according to our data. Variant chr4-54274918-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.17 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00181 (275/152290) while in subpopulation SAS AF = 0.0232 (112/4830). AF 95% confidence interval is 0.0197. There are 3 homozygotes in GnomAd4. There are 162 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 275 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDGFRA	NM_006206.6	c.1731G>A	p.Pro577Pro	synonymous_variant	Exon 12 of 23	ENST00000257290.10	NP_006197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDGFRA	ENST00000257290.10	c.1731G>A	p.Pro577Pro	synonymous_variant	Exon 12 of 23	1	NM_006206.6	ENSP00000257290.5
PDGFRA	ENST00000509092.5	n.1549G>A		non_coding_transcript_exon_variant	Exon 11 of 15	1
PDGFRA	ENST00000509490.5	n.1731G>A		non_coding_transcript_exon_variant	Exon 12 of 18	1		ENSP00000424218.1
ENSG00000282278	ENST00000507166.5	c.1018-7G>A		splice_region_variant, intron_variant	Intron 12 of 23	2		ENSP00000423325.1

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 273 AN: 152172 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0225

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00348 AC: 874 AN: 251200 AF XY: 0.00444

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.00170

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00220 AC: 3210 AN: 1461800 Hom.: 48 Cov.: 33 AF XY: 0.00279 AC XY: 2032 AN XY: 727210

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.000805 AC: 36 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0199 AC: 1714 AN: 86246

European-Finnish (FIN) AF: 0.00251 AC: 134 AN: 53406

Middle Eastern (MID) AF: 0.0177 AC: 102 AN: 5768

European-Non Finnish (NFE) AF: 0.000931 AC: 1035 AN: 1111952

Other (OTH) AF: 0.00283 AC: 171 AN: 60392

GnomAD4 genome AF: 0.00181 AC: 275 AN: 152290 Hom.: 3 Cov.: 33 AF XY: 0.00218 AC XY: 162 AN XY: 74470

African (AFR) AF: 0.000217 AC: 9 AN: 41560

American (AMR) AF: 0.00118 AC: 18 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.0232 AC: 112 AN: 4830

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00144 AC: 98 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00169 Hom.: 1

Bravo AF: 0.00117

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.00338

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:2

Sep 22, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Variant was observed in a homozygous state in population databases more than expected for disease. Allele frequency is greater than expected for the disorder. A synonymous variant not located in a splice region. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Gastrointestinal stromal tumor Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 22, 2022

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Idiopathic hypereosinophilic syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 30, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	1.1
DANN	Benign	0.67
PhyloP100		-2.2
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs55830582; hg19: chr4-55141085; COSMIC: COSV104566536;