chr4-54273689-T-C

Variant names:

• chr4-54273689-T-C
• rs746397815
• NM_006206.6:c.1517T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001347828.2(PDGFRA):​c.1592T>C​(p.Leu531Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L531F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PDGFRA NM_001347828.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.202
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07643214).
• BP6: Variant 4-54273689-T-C is Benign according to our data. Variant chr4-54273689-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3416406.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347828.2. 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.1517T>C	p.Leu506Pro	missense	Exon 10 of 23	NP_006197.1
	PDGFRA	NM_001347828.2		c.1592T>C	p.Leu531Pro	missense	Exon 11 of 24	NP_001334757.1
	PDGFRA	NM_001347830.2		c.1556T>C	p.Leu519Pro	missense	Exon 10 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.1517T>C	p.Leu506Pro	missense	Exon 10 of 23	ENSP00000257290.5
	ENSG00000282278	ENST00000507166.5	TSL:2	c.1018-1236T>C		intron	N/A	ENSP00000423325.1
	PDGFRA	ENST00000509092.5	TSL:1	n.1335T>C		non_coding_transcript_exon	Exon 9 of 15

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250516 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461706 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727154

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 31

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Benign	0.67
DEOGEN2	Benign	0.043	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.20
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.14
Sift	Benign	0.27	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.26
MutPred		0.67		Loss of stability (P = 0.025)
MVP		0.36
MPC		0.52
ClinPred		0.022	T
GERP RS		-5.2
Varity_R		0.23
gMVP		0.73
Mutation Taster		=94/6	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: rs746397815; hg19: chr4-55139856;