rs397515631

Variant names:

• chr22-39231645-G-A
• rs397515631
• NM_002608.4:c.433C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-39231645-G-A
• chr22-39231645-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002608.4(PDGFB):​c.433C>T​(p.Gln145*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,260 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PDGFB NM_002608.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.09

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-39231645-G-A is Pathogenic according to our data. Variant chr22-39231645-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 75237.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-39231645-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDGFB	NM_002608.4	c.433C>T	p.Gln145*	stop_gained	Exon 4 of 7	ENST00000331163.11	NP_002599.1
PDGFB	NM_033016.3	c.388C>T	p.Gln130*	stop_gained	Exon 4 of 7		NP_148937.1
PDGFB	XM_047441393.1	c.340C>T	p.Gln114*	stop_gained	Exon 4 of 7		XP_047297349.1
PDGFB	XM_047441394.1	c.340C>T	p.Gln114*	stop_gained	Exon 4 of 7		XP_047297350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDGFB	ENST00000331163.11	c.433C>T	p.Gln145*	stop_gained	Exon 4 of 7	1	NM_002608.4	ENSP00000330382.6
PDGFB	ENST00000381551.8	c.388C>T	p.Gln130*	stop_gained	Exon 4 of 7	5		ENSP00000370963.4
PDGFB	ENST00000455790.5	c.340C>T	p.Gln114*	stop_gained	Exon 4 of 5	4		ENSP00000402306.1
PDGFB	ENST00000440375.1	c.340C>T	p.Gln114*	stop_gained	Exon 4 of 5	4		ENSP00000405780.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152260 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1425166 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 705746

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74382

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Basal ganglia calcification, idiopathic, 5 Pathogenic:1

Sep 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

May 20, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

De novo variant with confirmed parentage; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene; Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26599395, 23913003) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.85	D
Vest4		0.79
GERP RS		3.0

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: rs397515631; hg19: chr22-39627650;