chr5-150121305-G-A

Variant names:

• chr5-150121305-G-A
• rs1320275282
• NM_002609.4:c.2362C>T
• PDGFRB p.Arg788*

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACMG Germline Pathogenicity v2019). PM2_Supporting

The NM_002609.4(PDGFRB):c.2362C>T (p.Arg788*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.00000445 (AC=7) in the gnomAD database across 1,573,160 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000147. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: PDGFRB NM_002609.4 stop_gained
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.73
• Publications: 2 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: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• myofibromatosis, infantile, 1

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

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

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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
• ocular pterygium-digital keloid dysplasia syndrome

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000147 — borderline rare for AD/XL gene (threshold 0.0001) — PM2 supporting.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_002609.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PDGFRB NM_002609.4	MANE Select	c.2362C>T p.Arg788*	stop_gained	Exon 17 of 23	Prot: NP_002600.1 UniProt:
	PDGFRB NM_001355016.2		c.2170C>T p.Arg724*	stop_gained	Exon 16 of 22	Prot: NP_001341945.1
	PDGFRB NM_001355017.2		c.1879C>T p.Arg627*	stop_gained	Exon 17 of 23	Prot: NP_001341946.1

PDGFRB NM_002609.4

MANE Select

HGVSc / HGVSpc.2362C>Tp.Arg788*

Exon rankExon 17 of 23

stop_gained

Prot: NP_002600.1UniProt: P09619-1

PDGFRB NM_001355016.2

HGVSc / HGVSpc.2170C>Tp.Arg724*

Exon rankExon 16 of 22

stop_gained

Prot: NP_001341945.1

PDGFRB NM_001355017.2

HGVSc / HGVSpc.1879C>Tp.Arg627*

Exon rankExon 17 of 23

stop_gained

Prot: NP_001341946.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PDGFRB ENST00000261799.9	TSL:1MANE Select	c.2362C>T p.Arg788*	stop_gained	Exon 17 of 23	Prot: ENSP00000261799.4 UniProt:
	PDGFRB ENST00000520579.5	TSL:1	n.*1676C>T	3_prime_UTR	Exon 17 of 23	Prot: ENSP00000430026.1 UniProt:
	PDGFRB ENST00000520579.5	TSL:1	n.*1676C>T	non_coding_transcript_exon	Exon 17 of 23	Prot: ENSP00000430026.1 UniProt:

PDGFRB ENST00000261799.9

TSL:1MANE Select

HGVSc / HGVSpc.2362C>Tp.Arg788*

Exon rankExon 17 of 23

stop_gained

Prot: ENSP00000261799.4UniProt: P09619-1

PDGFRB ENST00000520579.5

TSL:1

HGVSc / HGVSpn.*1676C>T

Exon rankExon 17 of 23

3_prime_UTR

Prot: ENSP00000430026.1UniProt: E5RH16

PDGFRB ENST00000520579.5

TSL:1

HGVSc / HGVSpn.*1676C>T

Exon rankExon 17 of 23

non_coding_transcript_exon

Prot: ENSP00000430026.1UniProt: E5RH16

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152124	Cov:32
GnomAD4 exome	AF: 0.00000422	AC:6	Hom:0	AN:1421036	Cov:27
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152124	Cov:32
TOPMed (Bravo)	AF: 0.00000756	AC:2	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000594	AC:1	Hom:0	AN:16840	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.00	0	28844
SCHEMA(Schizophrenia)	0.0000147	1	67848	0.00	0	133304

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	35
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	38
DANN	Uncertain	0.98
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.011
FATHMM_MKL	Benign	0.37	N
GPN-Star LLR	N/A	-8.1
GPN-Star score	N/A	8.1
Mutation Taster	N/A	11/189	disease causing (fs/PTC)
PhyloP100	Benign	2.7

Showing 12 of 12 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.040
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1320275282;

hg19: chr5-149500868;

COSMIC: COSV55806242;

COSMIC: COSV55806242;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar