rs2229558

chr5-150132844-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002609.4(PDGFRB):c.1033C>T(p.Pro345Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,610,196 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P345L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0081 (7 hom., cov: 33)
  • Exomes 𝑓: 0.012 (149 hom.)
• Consequence: PDGFRB NM_002609.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.06

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009585023).
• BP6: Variant 5-150132844-G-A is Benign according to our data. Variant chr5-150132844-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150132844-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00805 (1227/152394) while in subpopulation NFE AF= 0.0133 (905/68040). AF 95% confidence interval is 0.0126. There are 7 homozygotes in gnomad4. There are 571 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1228 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDGFRB	NM_002609.4	c.1033C>T	p.Pro345Ser	missense_variant	7/23	ENST00000261799.9
PDGFRB	NM_001355016.2	c.841C>T	p.Pro281Ser	missense_variant	6/22
PDGFRB	NM_001355017.2	c.550C>T	p.Pro184Ser	missense_variant	7/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDGFRB	ENST00000261799.9	c.1033C>T	p.Pro345Ser	missense_variant	7/23	1	NM_002609.4	P1
PDGFRB	ENST00000520579.5	c.*347C>T		3_prime_UTR_variant, NMD_transcript_variant	7/23	1

Frequencies

GnomAD3 genomes AF: 0.00806 AC: 1228 AN: 152276 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00736 AC: 1780 AN: 241984 Hom.: 9 AF XY: 0.00731 AC XY: 959 AN XY: 131208

Gnomad AFR exome AF: 0.00221

Gnomad AMR exome AF: 0.00545

Gnomad ASJ exome AF: 0.000304

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00146

Gnomad FIN exome AF: 0.00316

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.00756

GnomAD4 exome AF: 0.0120 AC: 17500 AN: 1457802 Hom.: 149 Cov.: 32 AF XY: 0.0116 AC XY: 8398 AN XY: 724840

Gnomad4 AFR exome AF: 0.00162

Gnomad4 AMR exome AF: 0.00554

Gnomad4 ASJ exome AF: 0.000307

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00169

Gnomad4 FIN exome AF: 0.00367

Gnomad4 NFE exome AF: 0.0145

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.00805 AC: 1227 AN: 152394 Hom.: 7 Cov.: 33 AF XY: 0.00766 AC XY: 571 AN XY: 74528

Gnomad4 AFR AF: 0.00269

Gnomad4 AMR AF: 0.0101

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.0133

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.0106 Hom.: 24

Bravo AF: 0.00802

TwinsUK AF: 0.0156 AC: 58

ALSPAC AF: 0.0184 AC: 71

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0109 AC: 94

ExAC AF: 0.00695 AC: 843

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 27, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PDGFRB: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 2019	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

-

- -

Basal ganglia calcification, idiopathic, 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Apr 08, 2019

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

Myeloproliferative disorder, chronic, with eosinophilia Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Infantile myofibromatosis;C1866182:Acroosteolysis-keloid-like lesions-premature aging syndrome;C3554321:Basal ganglia calcification, idiopathic, 4;C4225270:Skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	14
Dann	Benign	0.96
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.049
Sift	Benign	0.21	T
Sift4G	Benign	0.48	T
Polyphen		0.024	B
Vest4		0.20
MVP		0.28
MPC		0.24
ClinPred		0.0020	T
GERP RS		2.6
Varity_R		0.055
gMVP		0.54

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: rs2229558; hg19: chr5-149512407; COSMIC: COSV55801314; COSMIC: COSV55801314;