5-150124275-G-T

Position:

• chr5-150124275-G-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_002609.4(PDGFRB):​c.1998C>A​(p.Asn666Lys) variant causes a missense change. 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 Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N666H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PDGFRB NM_002609.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.87

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PS1: Transcript NM_002609.4 (PDGFRB) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-150124277-T-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 5-150124275-G-T is Pathogenic according to our data. Variant chr5-150124275-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 218935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150124275-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDGFRB	NM_002609.4	c.1998C>A	p.Asn666Lys	missense_variant	14/23	ENST00000261799.9	NP_002600.1
PDGFRB	NM_001355016.2	c.1806C>A	p.Asn602Lys	missense_variant	13/22		NP_001341945.1
PDGFRB	NM_001355017.2	c.1515C>A	p.Asn505Lys	missense_variant	14/23		NP_001341946.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDGFRB	ENST00000261799.9	c.1998C>A	p.Asn666Lys	missense_variant	14/23	1	NM_002609.4	ENSP00000261799	P1
PDGFRB	ENST00000520579.5	c.*1312C>A		3_prime_UTR_variant, NMD_transcript_variant	14/23	1		ENSP00000430026
PDGFRB	ENST00000520229.1	n.633C>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myofibromatosis, infantile, 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Feb 12, 2013

This mutation has been found in two myofibromas from one of the affected familial cases. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Jan 21, 2022

The PDGFRB p.Asn666Lys variant has been previously reported in the somatic state in multiple patients with infantile myofibromatosis (OMIM #228550) (PMID: 28334876 and others). The p.Asn666Lys variant is in the N-terminal lobe of the kinase domain of the PDGFRB protein and results in constitutive activation of downstream signaling (PMID: 28334876). This variant was identified in 35% of reads, suggesting somatic origin. Although the p.Asn666Lys variant has only been reported in the somatic state, constitutional activating variants in PDGFRB have been previously reported (PMID: 28334876 and others). -

Infantile myofibromatosis Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Demoulin lab, University of Louvain

Feb 01, 2017

This mutation was found in two patients with myofibromatosis in our cohort and has been reported by others. It strongly activates PDGFRB signaling in cell culture (gain of function). It was associated with other mutations in the same gene: in one patient, it was associated with c.1696T>C (p.W566R) and in a second case, with c.1681C>T (p.R561C). Another variant, c.1998C>G, leads to the same amino acid change (p.N666K). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	0.20	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.78		Gain of methylation at N666 (P = 0.013);
MVP		0.84
MPC		1.2
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.92
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.23		Position offset: -25

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs864309711; hg19: chr5-149503838; COSMIC: COSV55804407; COSMIC: COSV55804407;