5-150124275-G-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1PM2PM5PP3_StrongPP5_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 the same amino acid substitution has been previously reported as Pathogenic in 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

Scores

10
7
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.87
Variant links:
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]

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ACMG classification

Classification made for transcript

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 rank MANE Protein UniProt
PDGFRBNM_002609.4 linkc.1998C>A p.Asn666Lys missense_variant Exon 14 of 23 ENST00000261799.9 NP_002600.1 P09619-1Q59F04
PDGFRBNM_001355016.2 linkc.1806C>A p.Asn602Lys missense_variant Exon 13 of 22 NP_001341945.1
PDGFRBNM_001355017.2 linkc.1515C>A p.Asn505Lys missense_variant Exon 14 of 23 NP_001341946.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PDGFRBENST00000261799.9 linkc.1998C>A p.Asn666Lys missense_variant Exon 14 of 23 1 NM_002609.4 ENSP00000261799.4 P09619-1
PDGFRBENST00000520579.5 linkn.*1312C>A non_coding_transcript_exon_variant Exon 14 of 23 1 ENSP00000430026.1 E5RH16
PDGFRBENST00000520579.5 linkn.*1312C>A 3_prime_UTR_variant Exon 14 of 23 1 ENSP00000430026.1 E5RH16
PDGFRBENST00000520229.1 linkn.633C>A non_coding_transcript_exon_variant Exon 2 of 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
LINK: link

Submissions by phenotype

Myofibromatosis, infantile, 1 Pathogenic:1
Feb 12, 2013
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

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

not provided Pathogenic:1
Jan 21, 2022
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Feb 01, 2017
Demoulin lab, University of Louvain
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

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
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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