5-150129945-G-C

Variant names:

• chr5-150129945-G-C
• rs74943037
• NM_002609.4:c.1391C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002609.4(PDGFRB):​c.1391C>G​(p.Thr464Arg) 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 1,461,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T464M) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PDGFRB NM_002609.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.608
• Publications: 9 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13852921).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDGFRB	NM_002609.4	c.1391C>G	p.Thr464Arg	missense_variant	Exon 10 of 23	ENST00000261799.9	NP_002600.1
PDGFRB	NM_001355016.2	c.1199C>G	p.Thr400Arg	missense_variant	Exon 9 of 22		NP_001341945.1
PDGFRB	NM_001355017.2	c.908C>G	p.Thr303Arg	missense_variant	Exon 10 of 23		NP_001341946.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDGFRB	ENST00000261799.9	c.1391C>G	p.Thr464Arg	missense_variant	Exon 10 of 23	1	NM_002609.4	ENSP00000261799.4
PDGFRB	ENST00000520579.5	n.*705C>G		non_coding_transcript_exon_variant	Exon 10 of 23	1		ENSP00000430026.1
PDGFRB	ENST00000520579.5	n.*705C>G		3_prime_UTR_variant	Exon 10 of 23	1		ENSP00000430026.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461560 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727096

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

American (AMR) AF: 0.00 AC: 0 AN: 44722

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: 53138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 76

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	4.7
DANN	Benign	0.83
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.61
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.39
Sift	Benign	0.29	T
Sift4G	Benign	0.22	T
Polyphen		0.0020	B
Vest4		0.20
MutPred		0.20		Loss of glycosylation at T464 (P = 0.052);
MVP		0.89
MPC		0.26
ClinPred		0.37	T
GERP RS		3.8
Varity_R		0.11
gMVP		0.57
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs74943037; hg19: chr5-149509508;