chr4-54267677-A-T

Position:

• chr4-54267677-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_006206.6(PDGFRA):​c.1057A>T​(p.Asn353Tyr) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDGFRA NM_006206.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.12

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity PGFRA_HUMAN
• 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, 0.92

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDGFRA	NM_006206.6	c.1057A>T	p.Asn353Tyr	missense_variant	7/23	ENST00000257290.10	NP_006197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDGFRA	ENST00000257290.10	c.1057A>T	p.Asn353Tyr	missense_variant	7/23	1	NM_006206.6	ENSP00000257290.5
ENSG00000282278	ENST00000507166.5	c.1018-7248A>T		intron_variant		2		ENSP00000423325.1
PDGFRA	ENST00000509092.5	n.875A>T		non_coding_transcript_exon_variant	6/15	1
PDGFRA	ENST00000509490.5	n.1057A>T		non_coding_transcript_exon_variant	7/18	1		ENSP00000424218.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250694 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135480

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gastrointestinal stromal tumor Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2023

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PDGFRA protein function. ClinVar contains an entry for this variant (Variation ID: 568803). This variant has not been reported in the literature in individuals affected with PDGFRA-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 353 of the PDGFRA protein (p.Asn353Tyr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.8	M
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.030	D
Polyphen		0.97	D
Vest4		0.55
MutPred		0.79		Loss of catalytic residue at K351 (P = 0.1083);
MVP		0.63
MPC		1.0
ClinPred		0.97	D
GERP RS		4.6
Varity_R		0.80
gMVP		0.55

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: rs139103850; hg19: chr4-55133844;