4-54274888-A-G

Variant names:

• chr4-54274888-A-G
• rs1873778
• NM_006206.6:c.1701A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006206.6(PDGFRA):​c.1701A>G​(p.Pro567Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.993 in 1,613,940 control chromosomes in the GnomAD database, including 795,435 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. P567P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.97 (71320 hom., cov: 31)
  • Exomes 𝑓: 1.0 (724115 hom.)
• Consequence: PDGFRA NM_006206.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.56
• Publications: 80 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: G2P, Ambry Genetics, Genomics England PanelApp
• 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=-0.98).
• BP6: Variant 4-54274888-A-G is Benign according to our data. Variant chr4-54274888-A-G is described in ClinVar as Benign. ClinVar VariationId is 259949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.56 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006206.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDGFRA	NM_006206.6	MANE Select	c.1701A>G	p.Pro567Pro	synonymous	Exon 12 of 23	NP_006197.1	P16234-1
	PDGFRA	NM_001347828.2		c.1776A>G	p.Pro592Pro	synonymous	Exon 13 of 24	NP_001334757.1
	PDGFRA	NM_001347830.2		c.1740A>G	p.Pro580Pro	synonymous	Exon 12 of 23	NP_001334759.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDGFRA	ENST00000257290.10	TSL:1 MANE Select	c.1701A>G	p.Pro567Pro	synonymous	Exon 12 of 23	ENSP00000257290.5	P16234-1
	ENSG00000282278	ENST00000507166.5	TSL:2	c.1018-37A>G		intron	N/A	ENSP00000423325.1	A0A0B4J203
	PDGFRA	ENST00000509092.5	TSL:1	n.1519A>G		non_coding_transcript_exon	Exon 11 of 15

Frequencies

GnomAD3 genomes AF: 0.967 AC: 147117 AN: 152124 Hom.: 71292 Cov.: 31

Gnomad AFR AF: 0.890

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.985

Gnomad ASJ AF: 0.993

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.971

GnomAD2 exomes AF: 0.990 AC: 248680 AN: 251180 AF XY: 0.992

Gnomad AFR exome AF: 0.885

Gnomad AMR exome AF: 0.991

Gnomad ASJ exome AF: 0.994

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.992

GnomAD4 exome AF: 0.995 AC: 1454661 AN: 1461698 Hom.: 724115 Cov.: 44 AF XY: 0.996 AC XY: 723988 AN XY: 727152

African (AFR) AF: 0.877 AC: 29369 AN: 33474

American (AMR) AF: 0.990 AC: 44272 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.993 AC: 25966 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39699 AN: 39700

South Asian (SAS) AF: 0.999 AC: 86208 AN: 86258

European-Finnish (FIN) AF: 1.00 AC: 53413 AN: 53416

Middle Eastern (MID) AF: 0.985 AC: 5681 AN: 5768

European-Non Finnish (NFE) AF: 0.999 AC: 1110410 AN: 1111836

Other (OTH) AF: 0.988 AC: 59643 AN: 60386

GnomAD4 genome AF: 0.967 AC: 147194 AN: 152242 Hom.: 71320 Cov.: 31 AF XY: 0.968 AC XY: 72095 AN XY: 74440

African (AFR) AF: 0.889 AC: 36916 AN: 41522

American (AMR) AF: 0.985 AC: 15055 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.993 AC: 3445 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5159 AN: 5160

South Asian (SAS) AF: 0.999 AC: 4813 AN: 4818

European-Finnish (FIN) AF: 1.00 AC: 10618 AN: 10618

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.998 AC: 67935 AN: 68044

Other (OTH) AF: 0.971 AC: 2053 AN: 2114

Alfa AF: 0.984 Hom.: 64981

Bravo AF: 0.961

Asia WGS AF: 0.986 AC: 3430 AN: 3478

EpiCase AF: 0.998

EpiControl AF: 0.998

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Gastrointestinal stromal tumor (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Carcinoma of colon (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Idiopathic hypereosinophilic syndrome (1)
-	-	1	Squamous cell lung carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.093
DANN	Benign	0.40
PhyloP100		-3.6
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1873778; hg19: chr4-55141055; COSMIC: COSV99955338; COSMIC: COSV99955338;