rs1057519812

Positions:

• chr4-54277977-T-C
• chr4-54277977-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_006206.6(PDGFRA):​c.1973T>C​(p.Val658Ala) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V658L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PDGFRA NM_006206.6 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.95

Genes affected

PDGFRA (HGNC:8803): (platelet derived growth factor receptor alpha) This gene encodes 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 or a heterodimer, composed of both platelet-derived growth factor receptor alpha and beta polypeptides. Studies suggest that this gene plays a role in organ development, wound healing, and tumor progression. Mutations in this gene have been associated with idiopathic hypereosinophilic syndrome, somatic and familial gastrointestinal stromal tumors, and a variety of other cancers. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_006206.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PDGFRA. . Gene score misZ 1.9401 (greater than the threshold 3.09). Trascript score misZ 3.4078 (greater than threshold 3.09). GenCC has associacion of gene with congenital heart disease, polyps, multiple and recurrent inflammatory fibroid, gastrointestinal, gastrointestinal stromal tumor, isolated cleft palate.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 4-54277977-T-C is Pathogenic according to our data. Variant chr4-54277977-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376182.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDGFRA	NM_006206.6	c.1973T>C	p.Val658Ala	missense_variant	14/23	ENST00000257290.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDGFRA	ENST00000257290.10	c.1973T>C	p.Val658Ala	missense_variant	14/23	1	NM_006206.6	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Melanoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Dec 26, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	.;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	T;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.1	.;M
MutationTaster	Benign	0.73	D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-2.7	D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	.;D
Vest4		0.87
MutPred		0.86		.;Loss of stability (P = 0.0265);
MVP		0.91
MPC		1.2
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.67
gMVP		0.89

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: rs1057519812; hg19: chr4-55144144;