chr4-54258769-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_006206.6(PDGFRA):ā€‹c.1A>Gā€‹(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000657 in 152,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)

Consequence

PDGFRA
NM_006206.6 start_lost

Scores

7
6
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.43
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PDGFRANM_006206.6 linkuse as main transcriptc.1A>G p.Met1? start_lost 2/23 ENST00000257290.10 NP_006197.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PDGFRAENST00000257290.10 linkuse as main transcriptc.1A>G p.Met1? start_lost 2/231 NM_006206.6 ENSP00000257290 P1P16234-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152142
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
30
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152142
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Gastrointestinal stromal tumor Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 09, 2023This sequence change affects the initiator methionine of the PDGFRA mRNA. The next in-frame methionine is located at codon 61. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PDGFRA-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.28
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.040
T;.;T;.;.;T
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.90
D;D;T;D;D;D
M_CAP
Pathogenic
0.66
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D
MetaSVM
Uncertain
0.24
D
MutationTaster
Benign
1.0
D;D;D
PROVEAN
Benign
-0.65
N;N;N;N;N;N
REVEL
Uncertain
0.36
Sift
Pathogenic
0.0
D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D
Polyphen
0.71
P;D;.;.;.;.
Vest4
0.87
MutPred
0.94
Loss of glycosylation at P6 (P = 0.1128);Loss of glycosylation at P6 (P = 0.1128);.;Loss of glycosylation at P6 (P = 0.1128);Loss of glycosylation at P6 (P = 0.1128);Loss of glycosylation at P6 (P = 0.1128);
MVP
0.96
ClinPred
0.99
D
GERP RS
5.7
Varity_R
0.88
gMVP
0.76

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

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

Other links and lift over

dbSNP: rs1722515609; hg19: chr4-55124936; API