chr4-54267559-T-G

Variant names:

• chr4-54267559-T-G
• rs4358459
• NM_006206.6:c.939T>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.939T>G​(p.Gly313Gly) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G313G) has been classified as Likely 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:7
• Conservation: PhyloP100: -1.23
• Publications: 37 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=-0.9).
• BP6: Variant 4-54267559-T-G is Benign according to our data. Variant chr4-54267559-T-G is described in ClinVar as Benign. ClinVar VariationId 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.

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.939T>G	p.Gly313Gly	synonymous	Exon 7 of 23	NP_006197.1	P16234-1
	PDGFRA	NM_001347828.2		c.1014T>G	p.Gly338Gly	synonymous	Exon 8 of 24	NP_001334757.1
	PDGFRA	NM_001347830.2		c.978T>G	p.Gly326Gly	synonymous	Exon 7 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.939T>G	p.Gly313Gly	synonymous	Exon 7 of 23	ENSP00000257290.5	P16234-1
	ENSG00000282278	ENST00000507166.5	TSL:2	c.1018-7366T>G		intron	N/A	ENSP00000423325.1	A0A0B4J203
	PDGFRA	ENST00000509092.5	TSL:1	n.757T>G		non_coding_transcript_exon	Exon 6 of 15

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

GnomAD2 exomes AF: 0.185 AC: 46414 AN: 251130 AF XY: 0.175

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 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

African (AFR) AF: 0.251 AC: 8393 AN: 33464

American (AMR) AF: 0.395 AC: 17674 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0722 AC: 1887 AN: 26136

East Asian (EAS) AF: 0.167 AC: 6618 AN: 39696

South Asian (SAS) AF: 0.220 AC: 18974 AN: 86252

European-Finnish (FIN) AF: 0.121 AC: 6471 AN: 53414

Middle Eastern (MID) AF: 0.0914 AC: 527 AN: 5768

European-Non Finnish (NFE) AF: 0.126 AC: 140054 AN: 1111660

Other (OTH) AF: 0.145 AC: 8741 AN: 60372

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

African (AFR) AF: 0.252 AC: 10461 AN: 41440

American (AMR) AF: 0.284 AC: 4345 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0651 AC: 226 AN: 3470

East Asian (EAS) AF: 0.183 AC: 948 AN: 5170

South Asian (SAS) AF: 0.247 AC: 1191 AN: 4818

European-Finnish (FIN) AF: 0.125 AC: 1327 AN: 10576

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8303 AN: 67976

Other (OTH) AF: 0.148 AC: 311 AN: 2104

Alfa AF: 0.137 Hom.: 4594

Bravo AF: 0.193

Asia WGS AF: 0.247 AC: 859 AN: 3478

EpiCase AF: 0.113

EpiControl AF: 0.112

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)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Idiopathic hypereosinophilic syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.0
DANN	Benign	0.53
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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