4-54273560-C-T

Variant names:

• chr4-54273560-C-T
• rs375047532
• NM_006206.6:c.1388C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006206.6(PDGFRA):​c.1388C>T​(p.Thr463Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T463S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PDGFRA NM_006206.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.49

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]

ENSG00000282278 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25114286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDGFRA	NM_006206.6	c.1388C>T	p.Thr463Ile	missense_variant	Exon 10 of 23	ENST00000257290.10	NP_006197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDGFRA	ENST00000257290.10	c.1388C>T	p.Thr463Ile	missense_variant	Exon 10 of 23	1	NM_006206.6	ENSP00000257290.5
ENSG00000282278	ENST00000507166.5	c.1018-1365C>T		intron_variant	Intron 12 of 23	2		ENSP00000423325.1
PDGFRA	ENST00000509092.5	n.1206C>T		non_coding_transcript_exon_variant	Exon 9 of 15	1
PDGFRA	ENST00000509490.5	n.1388C>T		non_coding_transcript_exon_variant	Exon 10 of 18	1		ENSP00000424218.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gastrointestinal stromal tumor Uncertain:1

Sep 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 568659). This variant has not been reported in the literature in individuals affected with PDGFRA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 463 of the PDGFRA protein (p.Thr463Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.016	D
Sift4G	Benign	0.079	T
Polyphen		0.12	B
Vest4		0.34
MutPred		0.39		Loss of sheet (P = 0.0817);
MVP		0.74
MPC		0.35
ClinPred		0.25	T
GERP RS		5.5
Varity_R		0.15
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs375047532; hg19: chr4-55139727;