5-150115797-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002609.4(PDGFRB):c.3287C>T(p.Ala1096Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,611,438 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1096A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (6 hom.)
• Consequence: PDGFRB NM_002609.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.384

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004463464).
• BP6: Variant 5-150115797-G-A is Benign according to our data. Variant chr5-150115797-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 707132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150115797-G-A is described in Lovd as [Likely_benign]. Variant chr5-150115797-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00253 (386/152328) while in subpopulation NFE AF= 0.00351 (239/68036). AF 95% confidence interval is 0.00315. There are 0 homozygotes in gnomad4. There are 179 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 386 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDGFRB	NM_002609.4	c.3287C>T	p.Ala1096Val	missense_variant	23/23	ENST00000261799.9
PDGFRB	NM_001355016.2	c.3095C>T	p.Ala1032Val	missense_variant	22/22
PDGFRB	NM_001355017.2	c.2804C>T	p.Ala935Val	missense_variant	23/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDGFRB	ENST00000261799.9	c.3287C>T	p.Ala1096Val	missense_variant	23/23	1	NM_002609.4	P1
PDGFRB	ENST00000520579.5	c.*2601C>T		3_prime_UTR_variant, NMD_transcript_variant	23/23	1

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 386 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00351

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00301 AC: 746 AN: 247568 Hom.: 0 AF XY: 0.00302 AC XY: 405 AN XY: 134138

Gnomad AFR exome AF: 0.000688

Gnomad AMR exome AF: 0.00235

Gnomad ASJ exome AF: 0.00471

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00119

Gnomad FIN exome AF: 0.00471

Gnomad NFE exome AF: 0.00404

Gnomad OTH exome AF: 0.00349

GnomAD4 exome AF: 0.00306 AC: 4471 AN: 1459110 Hom.: 6 Cov.: 32 AF XY: 0.00300 AC XY: 2176 AN XY: 725682

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.00238

Gnomad4 ASJ exome AF: 0.00449

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00114

Gnomad4 FIN exome AF: 0.00508

Gnomad4 NFE exome AF: 0.00332

Gnomad4 OTH exome AF: 0.00290

GnomAD4 genome AF: 0.00253 AC: 386 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.00240 AC XY: 179 AN XY: 74480

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00442

Gnomad4 NFE AF: 0.00351

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00314 Hom.: 1

Bravo AF: 0.00233

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00306 AC: 371

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00423

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2021	This variant is associated with the following publications: (PMID: 29084058, 26599395, 24796542) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Myofibromatosis, infantile, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Infantile myofibromatosis;C1866182:Acroosteolysis-keloid-like lesions-premature aging syndrome;C3554321:Basal ganglia calcification, idiopathic, 4;C4225270:Skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	7.0
Dann	Benign	0.97
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.12
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.056	T
Polyphen		0.18	B
Vest4		0.036
MVP		0.33
MPC		0.36
ClinPred		0.0038	T
GERP RS		1.3
Varity_R		0.032
gMVP		0.17

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: rs114435947; hg19: chr5-149495360; COSMIC: COSV53827777; COSMIC: COSV53827777;