rs1060499540

Positions:

• chr5-150120925-T-A
• chr5-150120925-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_002609.4(PDGFRB):​c.2549A>T​(p.Asp850Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDGFRB NM_002609.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02

Genes affected

PDGFRB (HGNC:8804): (platelet derived growth factor receptor beta) The protein encoded by this gene is 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 (PDGFB or PDGFD) or a heterodimer (PDGFA and PDGFB). This gene is essential for normal development of the cardiovascular system and aids in rearrangement of the actin cytoskeleton. This gene is flanked on chromosome 5 by the genes for granulocyte-macrophage colony-stimulating factor and macrophage-colony stimulating factor receptor; all three genes may be implicated in the 5-q syndrome. A translocation between chromosomes 5 and 12, that fuses this gene to that of the ETV6 gene, results in chronic myeloproliferative disorder with eosinophilia. [provided by RefSeq, Aug 2017]

PDGFRB (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 5-150120925-T-A is Pathogenic according to our data. Variant chr5-150120925-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 375681.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-150120925-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDGFRB	NM_002609.4	c.2549A>T	p.Asp850Val	missense_variant	18/23	ENST00000261799.9	NP_002600.1
PDGFRB	NM_001355016.2	c.2357A>T	p.Asp786Val	missense_variant	17/22		NP_001341945.1
PDGFRB	NM_001355017.2	c.2066A>T	p.Asp689Val	missense_variant	18/23		NP_001341946.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDGFRB	ENST00000261799.9	c.2549A>T	p.Asp850Val	missense_variant	18/23	1	NM_002609.4	ENSP00000261799.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Infantile myofibromatosis Pathogenic:1

Pathogenic, criteria provided, single submitter

in vitro;research

Demoulin lab, University of Louvain

Dec 01, 2016

This somatic mutation was found in two patients with myofibromatosis. It strongly activates PDGFRB signaling in cell culture (gain of function). It is homologous to pathogenic mutations in receptors of the same family, such as PDGFRA D842V and KIT D816V (in gastrointestinal stromal tumors). We sequenced PDGFRB in myofibromatosis cases using the Ion Torrent technology. All variants were confirmed by an alternative method (allele specific PCR or Sanger sequencing). Mutants were functionally characterized in experiments based on cell transfection. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	0.64	N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.98	D
Vest4		0.99
MutPred		0.82		Gain of MoRF binding (P = 0.0609);
MVP		0.97
MPC		1.4
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.68
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060499540; hg19: chr5-149500488; COSMIC: COSV55807424; COSMIC: COSV55807424;