rs2228439

Variant names:

• chr5-150132073-C-G
• rs2228439
• NM_002609.4:c.1149G>C
• PDGFRB p.Leu383Leu

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_002609.4(PDGFRB):​c.1149G>C​(p.Leu383Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,606,436 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (5 hom., cov: 32)
  • Exomes 𝑓: 0.011 (103 hom.)
• Consequence: PDGFRB NM_002609.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.593
• Publications: 4 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, Labcorp Genetics (formerly Invitae), Orphanet
• myofibromatosis, infantile, 1

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

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

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 5-150132073-C-G is Benign according to our data. Variant chr5-150132073-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.593 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00775 (1180/152310) while in subpopulation NFE AF = 0.0116 (790/68026). AF 95% confidence interval is 0.0109. There are 5 homozygotes in GnomAd4. There are 543 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1180 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDGFRB	NM_002609.4	MANE Select	c.1149G>C	p.Leu383Leu	synonymous	Exon 8 of 23	NP_002600.1	P09619-1
	PDGFRB	NM_001355016.2		c.957G>C	p.Leu319Leu	synonymous	Exon 7 of 22	NP_001341945.1
	PDGFRB	NM_001355017.2		c.666G>C	p.Leu222Leu	synonymous	Exon 8 of 23	NP_001341946.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDGFRB	ENST00000261799.9	TSL:1 MANE Select	c.1149G>C	p.Leu383Leu	synonymous	Exon 8 of 23	ENSP00000261799.4	P09619-1
	PDGFRB	ENST00000520579.5	TSL:1	n.*463G>C		non_coding_transcript_exon	Exon 8 of 23	ENSP00000430026.1	E5RH16
	PDGFRB	ENST00000520579.5	TSL:1	n.*463G>C		3_prime_UTR	Exon 8 of 23	ENSP00000430026.1	E5RH16

Frequencies

GnomAD3 genomes AF: 0.00775 AC: 1180 AN: 152192 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00777 AC: 1948 AN: 250762 AF XY: 0.00770

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00325

Gnomad ASJ exome AF: 0.0198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0136

Gnomad NFE exome AF: 0.0110

Gnomad OTH exome AF: 0.00981

GnomAD4 exome AF: 0.0107 AC: 15524 AN: 1454126 Hom.: 103 Cov.: 28 AF XY: 0.0104 AC XY: 7516 AN XY: 723928

African (AFR) AF: 0.00189 AC: 63 AN: 33326

American (AMR) AF: 0.00369 AC: 165 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0206 AC: 537 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.000430 AC: 37 AN: 86124

European-Finnish (FIN) AF: 0.0151 AC: 807 AN: 53398

Middle Eastern (MID) AF: 0.00209 AC: 12 AN: 5752

European-Non Finnish (NFE) AF: 0.0120 AC: 13310 AN: 1104942

Other (OTH) AF: 0.00986 AC: 593 AN: 60164

GnomAD4 genome AF: 0.00775 AC: 1180 AN: 152310 Hom.: 5 Cov.: 32 AF XY: 0.00729 AC XY: 543 AN XY: 74474

African (AFR) AF: 0.00207 AC: 86 AN: 41558

American (AMR) AF: 0.00562 AC: 86 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 61 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.0121 AC: 129 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0116 AC: 790 AN: 68026

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.0107 Hom.: 3

Bravo AF: 0.00733

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0121

EpiControl AF: 0.0112

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	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 (1)
-	-	1	Myeloproliferative disorder, chronic, with eosinophilia (1)
-	-	1	Myofibromatosis, infantile, 1 (1)
-	-	1	PDGFRB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	1.0
DANN	Benign	0.58
PhyloP100		0.59
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2228439;

hg19: chr5-149511636;