rs1060499541

chr5-150126578-A-AATC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The NM_002609.4(PDGFRB):c.1615_1616insGAT(p.Ile538_Leu539insArg) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDGFRB NM_002609.4 inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.00

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_002609.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_002609.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 5-150126578-A-AATC is Pathogenic according to our data. Variant chr5-150126578-A-AATC is described in ClinVar as [Pathogenic]. Clinvar id is 375557.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDGFRB	NM_002609.4	c.1615_1616insGAT	p.Ile538_Leu539insArg	inframe_insertion	11/23	ENST00000261799.9
PDGFRB	NM_001355016.2	c.1423_1424insGAT	p.Ile474_Leu475insArg	inframe_insertion	10/22
PDGFRB	NM_001355017.2	c.1132_1133insGAT	p.Ile377_Leu378insArg	inframe_insertion	11/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDGFRB	ENST00000261799.9	c.1615_1616insGAT	p.Ile538_Leu539insArg	inframe_insertion	11/23	1	NM_002609.4	P1
PDGFRB	ENST00000520579.5	c.*929_*930insGAT		3_prime_UTR_variant, NMD_transcript_variant	11/23	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Infantile myofibromatosis Pathogenic:1

Pathogenic, no assertion criteria provided

in vitro;research

Demoulin lab, University of Louvain

Dec 01, 2016

This mutation was found in two patients with myofibromatosis. It strongly activates PDGFRB signaling in cell culture (gain of function). 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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060499541; hg19: chr5-149506141;