chr4-54263664-C-T

Variant names:

• chr4-54263664-C-T
• rs55947416
• NM_006206.6:c.368-3C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_006206.6(PDGFRA):​c.368-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0629 in 1,612,354 control chromosomes in the GnomAD database, including 3,637 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (226 hom., cov: 32)
  • Exomes 𝑓: 0.065 (3411 hom.)
• Consequence: PDGFRA NM_006206.6 splice_region, intron
• Scores: Splicing: ADA: 0.02828
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.39
• Publications: 13 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21).
• BP6: Variant 4-54263664-C-T is Benign according to our data. Variant chr4-54263664-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0692 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.368-3C>T		splice_region intron	N/A	NP_006197.1
	PDGFRA	NM_001347828.2		c.443-3C>T		splice_region intron	N/A	NP_001334757.1
	PDGFRA	NM_001347830.2		c.407-3C>T		splice_region intron	N/A	NP_001334759.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDGFRA	ENST00000257290.10	TSL:1 MANE Select	c.368-3C>T		splice_region intron	N/A	ENSP00000257290.5
	ENSG00000282278	ENST00000507166.5	TSL:2	c.1018-11261C>T		intron	N/A	ENSP00000423325.1
	PDGFRA	ENST00000508170.5	TSL:1	c.368-3C>T		splice_region intron	N/A	ENSP00000425648.1

Frequencies

GnomAD3 genomes AF: 0.0461 AC: 7019 AN: 152126 Hom.: 226 Cov.: 32

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0423

Gnomad ASJ AF: 0.0332

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0406

Gnomad FIN AF: 0.0607

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0709

Gnomad OTH AF: 0.0436

GnomAD2 exomes AF: 0.0488 AC: 12265 AN: 251276 AF XY: 0.0504

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.0246

Gnomad ASJ exome AF: 0.0348

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.0628

Gnomad NFE exome AF: 0.0684

Gnomad OTH exome AF: 0.0489

GnomAD4 exome AF: 0.0646 AC: 94328 AN: 1460110 Hom.: 3411 Cov.: 32 AF XY: 0.0644 AC XY: 46750 AN XY: 726448

African (AFR) AF: 0.00938 AC: 314 AN: 33470

American (AMR) AF: 0.0270 AC: 1209 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0347 AC: 907 AN: 26122

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39698

South Asian (SAS) AF: 0.0490 AC: 4228 AN: 86236

European-Finnish (FIN) AF: 0.0653 AC: 3487 AN: 53412

Middle Eastern (MID) AF: 0.0271 AC: 156 AN: 5764

European-Non Finnish (NFE) AF: 0.0726 AC: 80655 AN: 1110346

Other (OTH) AF: 0.0556 AC: 3358 AN: 60348

GnomAD4 genome AF: 0.0461 AC: 7015 AN: 152244 Hom.: 226 Cov.: 32 AF XY: 0.0455 AC XY: 3388 AN XY: 74440

African (AFR) AF: 0.0118 AC: 490 AN: 41550

American (AMR) AF: 0.0422 AC: 646 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0332 AC: 115 AN: 3466

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.0406 AC: 196 AN: 4822

European-Finnish (FIN) AF: 0.0607 AC: 643 AN: 10596

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0709 AC: 4820 AN: 68014

Other (OTH) AF: 0.0427 AC: 90 AN: 2110

Alfa AF: 0.0608 Hom.: 268

Bravo AF: 0.0409

Asia WGS AF: 0.0190 AC: 67 AN: 3478

EpiCase AF: 0.0649

EpiControl AF: 0.0636

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Gastrointestinal stromal tumor (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Idiopathic hypereosinophilic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	12
DANN	Benign	0.93
PhyloP100		2.4
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.028
dbscSNV1_RF	Benign	0.046
SpliceAI score (max)		0.070		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: rs55947416; hg19: chr4-55129831; COSMIC: COSV57265057; COSMIC: COSV57265057;