rs138008832

chr5-150123142-G-Achr5-150123142-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_Moderate BS1_Supporting BS2

The NM_002609.4(PDGFRB):c.2083C>T(p.Arg695Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 1,613,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R695H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: PDGFRB NM_002609.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 2.74

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_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000226 (330/1461410) while in subpopulation NFE AF= 0.000269 (299/1111704). AF 95% confidence interval is 0.000244. There are 0 homozygotes in gnomad4_exome. There are 167 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDGFRB	NM_002609.4	c.2083C>T	p.Arg695Cys	missense_variant	15/23	ENST00000261799.9
PDGFRB	NM_001355016.2	c.1891C>T	p.Arg631Cys	missense_variant	14/22
PDGFRB	NM_001355017.2	c.1600C>T	p.Arg534Cys	missense_variant	15/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDGFRB	ENST00000261799.9	c.2083C>T	p.Arg695Cys	missense_variant	15/23	1	NM_002609.4	P1
PDGFRB	ENST00000520579.5	c.*1397C>T		3_prime_UTR_variant, NMD_transcript_variant	15/23	1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000111 AC: 28 AN: 251344 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135860

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000226 AC: 330 AN: 1461410 Hom.: 0 Cov.: 31 AF XY: 0.000230 AC XY: 167 AN XY: 727060

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000269

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74362

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Basal ganglia calcification, idiopathic, 4 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Apr 15, 2019	- -
Likely pathogenic, no assertion criteria provided	research	Rademakers Lab, Mayo Clinic	Jan 01, 2012	Risk allele was found to induce deficient protein function in cell culture -

Cerebral palsy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Neurogenetics Research Program, University of Adelaide

Jun 10, 2021

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 01, 2023

Reported as a variant of uncertain significance in an individual with Alzheimer's disease (Lenglez et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26599395, 27776010, 25212438, 25686613, 28935882, 28298627, 24796542, 34494111, 31004414, 30805583, 29152850, Kaya_2023, 36469195, 33449152) -

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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 05, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 695 of the PDGFRB protein (p.Arg695Cys). This variant is present in population databases (rs138008832, gnomAD 0.02%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with basal ganglia calcification (PMID: 24796542, 34494111). ClinVar contains an entry for this variant (Variation ID: 135650). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PDGFRB protein function. Experimental studies have shown that this missense change affects PDGFRB function (PMID: 24796542, 34494111). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.63		Loss of disorder (P = 0.0321);
MVP		0.88
MPC		1.3
ClinPred		0.44	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs138008832; hg19: chr5-149502705;