chr22-39225734-G-C

Position:

• chr22-39225734-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_002608.4(PDGFB):​c.715C>G​(p.Leu239Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PDGFB NM_002608.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.88

Genes affected

PDGFB (HGNC:8800): (platelet derived growth factor subunit B) This gene encodes a member of the protein family comprised of both platelet-derived growth factors (PDGF) and vascular endothelial growth factors (VEGF). The encoded preproprotein is proteolytically processed to generate platelet-derived growth factor subunit B, which can homodimerize, or alternatively, heterodimerize with the related platelet-derived growth factor subunit A. These proteins bind and activate PDGF receptor tyrosine kinases, which play a role in a wide range of developmental processes. Mutations in this gene are associated with meningioma. Reciprocal translocations between chromosomes 22 and 17, at sites where this gene and that for collagen type 1, alpha 1 are located, are associated with dermatofibrosarcoma protuberans, a rare skin tumor. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33966166).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDGFB	NM_002608.4	c.715C>G	p.Leu239Val	missense_variant	6/7	ENST00000331163.11	NP_002599.1
PDGFB	NM_033016.3	c.670C>G	p.Leu224Val	missense_variant	6/7		NP_148937.1
PDGFB	XM_047441393.1	c.622C>G	p.Leu208Val	missense_variant	6/7		XP_047297349.1
PDGFB	XM_047441394.1	c.622C>G	p.Leu208Val	missense_variant	6/7		XP_047297350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDGFB	ENST00000331163.11	c.715C>G	p.Leu239Val	missense_variant	6/7	1	NM_002608.4	ENSP00000330382.6
PDGFB	ENST00000381551.8	c.670C>G	p.Leu224Val	missense_variant	6/7	5		ENSP00000370963.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461600 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 239 of the PDGFB protein (p.Leu239Val). This variant is present in population databases (rs775740429, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with PDGFB-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	0.14
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.44	N;N
REVEL	Benign	0.22
Sift	Uncertain	0.0040	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.47
MutPred		0.094		Gain of methylation at K236 (P = 0.0538);.;
MVP		0.51
MPC		1.2
ClinPred		0.73	D
GERP RS		5.3
Varity_R		0.13
gMVP		0.28

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: rs775740429; hg19: chr22-39621739;