NM_002609.4:c.1994T>C

Variant names:

• chr5-150124279-A-G
• rs1554108211
• NM_002609.4:c.1994T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_002609.4(PDGFRB):​c.1994T>C​(p.Val665Ala) 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 (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PDGFRB NM_002609.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• acroosteolysis-keloid-like lesions-premature aging syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• myofibromatosis, infantile, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• basal ganglia calcification, idiopathic, 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• bilateral striopallidodentate calcinosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile myofibromatosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary progressive mucinous histiocytosis

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_002609.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 5-150124279-A-G is Pathogenic according to our data. Variant chr5-150124279-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 495300.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002609.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDGFRB	NM_002609.4	MANE Select	c.1994T>C	p.Val665Ala	missense	Exon 14 of 23	NP_002600.1
	PDGFRB	NM_001355016.2		c.1802T>C	p.Val601Ala	missense	Exon 13 of 22	NP_001341945.1
	PDGFRB	NM_001355017.2		c.1511T>C	p.Val504Ala	missense	Exon 14 of 23	NP_001341946.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDGFRB	ENST00000261799.9	TSL:1 MANE Select	c.1994T>C	p.Val665Ala	missense	Exon 14 of 23	ENSP00000261799.4
	PDGFRB	ENST00000520579.5	TSL:1	n.*1308T>C		non_coding_transcript_exon	Exon 14 of 23	ENSP00000430026.1
	PDGFRB	ENST00000520579.5	TSL:1	n.*1308T>C		3_prime_UTR	Exon 14 of 23	ENSP00000430026.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Acroosteolysis-keloid-like lesions-premature aging syndrome Pathogenic:1

Nov 21, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.88		Loss of sheet (P = 0.0817)
MVP		0.90
MPC		1.3
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.60
gMVP		0.83
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1554108211; hg19: chr5-149503842; COSMIC: COSV55804346; COSMIC: COSV55804346;