rs397515632

Variant names:

• chr22-39231722-A-G
• rs397515632
• NM_002608.4:c.356T>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_002608.4(PDGFB):​c.356T>C​(p.Leu119Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDGFB NM_002608.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.95

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915
• PP5: Variant 22-39231722-A-G is Pathogenic according to our data. Variant chr22-39231722-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 75239.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-39231722-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDGFB	NM_002608.4	c.356T>C	p.Leu119Pro	missense_variant	Exon 4 of 7	ENST00000331163.11	NP_002599.1
PDGFB	NM_033016.3	c.311T>C	p.Leu104Pro	missense_variant	Exon 4 of 7		NP_148937.1
PDGFB	XM_047441393.1	c.263T>C	p.Leu88Pro	missense_variant	Exon 4 of 7		XP_047297349.1
PDGFB	XM_047441394.1	c.263T>C	p.Leu88Pro	missense_variant	Exon 4 of 7		XP_047297350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDGFB	ENST00000331163.11	c.356T>C	p.Leu119Pro	missense_variant	Exon 4 of 7	1	NM_002608.4	ENSP00000330382.6
PDGFB	ENST00000381551.8	c.311T>C	p.Leu104Pro	missense_variant	Exon 4 of 7	5		ENSP00000370963.4
PDGFB	ENST00000455790.5	c.263T>C	p.Leu88Pro	missense_variant	Exon 4 of 5	4		ENSP00000402306.1
PDGFB	ENST00000440375.1	c.263T>C	p.Leu88Pro	missense_variant	Exon 4 of 5	4		ENSP00000405780.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00649 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Basal ganglia calcification, idiopathic, 5 Pathogenic:1

Sep 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.4	M;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.6	D;D;D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;.;D
Polyphen		1.0	D;.;.;.
Vest4		0.95
MutPred		0.76		Loss of catalytic residue at L119 (P = 0.0026);.;.;.;
MVP		0.76
MPC		1.5
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
gMVP		0.99

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: rs397515632; hg19: chr22-39627727;