chr4-54289012-C-T

Variant names:

• chr4-54289012-C-T
• rs138519829
• NM_006206.6:c.2778C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The ENST00000257290.10(PDGFRA):​c.2778C>T​(p.Tyr926Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,604,072 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (24 hom.)
• Consequence: PDGFRA ENST00000257290.10 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.371
• Publications: 2 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 4-54289012-C-T is Benign according to our data. Variant chr4-54289012-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.371 with no splicing effect.
• BS2: High AC in GnomAd4 at 551 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000257290.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDGFRA	NM_006206.6	MANE Select	c.2778C>T	p.Tyr926Tyr	synonymous	Exon 21 of 23	NP_006197.1
	PDGFRA	NM_001347828.2		c.2853C>T	p.Tyr951Tyr	synonymous	Exon 22 of 24	NP_001334757.1
	PDGFRA	NM_001347830.2		c.2817C>T	p.Tyr939Tyr	synonymous	Exon 21 of 23	NP_001334759.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDGFRA	ENST00000257290.10	TSL:1 MANE Select	c.2778C>T	p.Tyr926Tyr	synonymous	Exon 21 of 23	ENSP00000257290.5
	ENSG00000282278	ENST00000507166.5	TSL:2	c.2058C>T	p.Tyr686Tyr	synonymous	Exon 22 of 24	ENSP00000423325.1

Frequencies

GnomAD3 genomes AF: 0.00364 AC: 553 AN: 152090 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0302

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.00416 AC: 1044 AN: 251196 AF XY: 0.00429

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0291

Gnomad NFE exome AF: 0.00264

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00303 AC: 4393 AN: 1451864 Hom.: 24 Cov.: 29 AF XY: 0.00300 AC XY: 2172 AN XY: 722998

African (AFR) AF: 0.000451 AC: 15 AN: 33286

American (AMR) AF: 0.000537 AC: 24 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00247 AC: 213 AN: 86068

European-Finnish (FIN) AF: 0.0286 AC: 1528 AN: 53414

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5734

European-Non Finnish (NFE) AF: 0.00225 AC: 2478 AN: 1102816

Other (OTH) AF: 0.00211 AC: 127 AN: 60096

GnomAD4 genome AF: 0.00362 AC: 551 AN: 152208 Hom.: 6 Cov.: 32 AF XY: 0.00462 AC XY: 344 AN XY: 74396

African (AFR) AF: 0.000409 AC: 17 AN: 41538

American (AMR) AF: 0.000131 AC: 2 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4822

European-Finnish (FIN) AF: 0.0302 AC: 320 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00287 AC: 195 AN: 68030

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.00227 Hom.: 1

Bravo AF: 0.00119

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.00311

EpiControl AF: 0.00178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	Gastrointestinal stromal tumor (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	-0.48
CADD	Benign	0.35
DANN	Benign	0.41
PhyloP100		-0.37
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs138519829; hg19: chr4-55155179; COSMIC: COSV57270746;