4-54264951-C-T

Variant names:

• chr4-54264951-C-T
• rs139913632
• NM_006206.6:c.661C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006206.6(PDGFRA):​c.661C>T​(p.Leu221Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00444 in 1,613,168 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L221R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0030 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (16 hom.)
• Consequence: PDGFRA NM_006206.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:14 O:1
• Conservation: PhyloP100: 0.908
• Publications: 19 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056384206).
• BP6: Variant 4-54264951-C-T is Benign according to our data. Variant chr4-54264951-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 452 Unknown,AD gene.

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.661C>T	p.Leu221Phe	missense	Exon 5 of 23	NP_006197.1	P16234-1
	PDGFRA	NM_001347828.2		c.736C>T	p.Leu246Phe	missense	Exon 6 of 24	NP_001334757.1
	PDGFRA	NM_001347830.2		c.700C>T	p.Leu234Phe	missense	Exon 5 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.661C>T	p.Leu221Phe	missense	Exon 5 of 23	ENSP00000257290.5	P16234-1
	PDGFRA	ENST00000508170.5	TSL:1	c.*995C>T		3_prime_UTR	Exon 4 of 4	ENSP00000425648.1	P16234-2
	ENSG00000282278	ENST00000507166.5	TSL:2	c.1018-9974C>T		intron	N/A	ENSP00000423325.1	A0A0B4J203

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 452 AN: 151866 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000702

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00171

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00531

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00343 AC: 863 AN: 251426 AF XY: 0.00365

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00569

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00459 AC: 6706 AN: 1461200 Hom.: 16 Cov.: 31 AF XY: 0.00455 AC XY: 3311 AN XY: 726950

African (AFR) AF: 0.000717 AC: 24 AN: 33454

American (AMR) AF: 0.00161 AC: 72 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00336 AC: 290 AN: 86234

European-Finnish (FIN) AF: 0.00187 AC: 100 AN: 53398

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5766

European-Non Finnish (NFE) AF: 0.00539 AC: 5989 AN: 1111466

Other (OTH) AF: 0.00364 AC: 220 AN: 60366

GnomAD4 genome AF: 0.00297 AC: 452 AN: 151968 Hom.: 3 Cov.: 32 AF XY: 0.00287 AC XY: 213 AN XY: 74256

African (AFR) AF: 0.000700 AC: 29 AN: 41446

American (AMR) AF: 0.00157 AC: 24 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00250 AC: 12 AN: 4802

European-Finnish (FIN) AF: 0.00171 AC: 18 AN: 10514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00531 AC: 361 AN: 67992

Other (OTH) AF: 0.00380 AC: 8 AN: 2106

Alfa AF: 0.00446 Hom.: 6

Bravo AF: 0.00279

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00376 AC: 456

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00485

EpiControl AF: 0.00474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	7	not provided (8)
-	-	3	Gastrointestinal stromal tumor (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Idiopathic hypereosinophilic syndrome (1)
1	-	-	Myeloproliferative neoplasm, unclassifiable (1)
-	-	1	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.91
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.21
Sift	Benign	0.053	T
Sift4G	Benign	0.061	T
Polyphen		0.25	B
Vest4		0.17
MVP		0.44
MPC		0.45
ClinPred		0.028	T
GERP RS		4.4
Varity_R		0.14
gMVP		0.51
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs139913632; hg19: chr4-55131118; COSMIC: COSV57270791;