4-54280441-T-G

Position:

chr4-54280441-T-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_006206.6(PDGFRA):c.2282T>G(p.Leu761Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000616 in 1,613,826 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00054 ( 12 hom. )

Consequence

PDGFRA
NM_006206.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 6.11

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]

PDGFRA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.0109345615).

BP6

Variant 4-54280441-T-G is Benign according to our data. Variant chr4-54280441-T-G is described in ClinVar as [Benign]. Clinvar id is 135016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 211 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDGFRA	NM_006206.6 linkuse as main transcript	c.2282T>G	p.Leu761Arg	missense_variant	16/23	ENST00000257290.10	NP_006197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDGFRA	ENST00000257290.10 linkuse as main transcript	c.2282T>G	p.Leu761Arg	missense_variant	16/23	1	NM_006206.6	ENSP00000257290	P1	P16234-1
PDGFRA	ENST00000507536.1 linkuse as main transcript	n.708T>G		non_coding_transcript_exon_variant	4/5	1
PDGFRA	ENST00000509092.5 linkuse as main transcript	n.2100T>G		non_coding_transcript_exon_variant	15/15	1
PDGFRA	ENST00000509490.5 linkuse as main transcript	c.*203T>G		3_prime_UTR_variant, NMD_transcript_variant	17/18	1		ENSP00000424218		P16234-3

Frequencies

GnomAD3 genomes

AF:

0.00133

AC:

202

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0122

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00227

AC:

569

AN:

251118

Hom.:

AF XY:

0.00183

AC XY:

249

AN XY:

135718

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0161

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.000536

AC:

783

AN:

1461450

Hom.:

Cov.:

AF XY:

0.000468

AC XY:

340

AN XY:

727056

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0159

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.000861

GnomAD4 genome

AF:

0.00138

AC:

211

AN:

152376

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

113

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.0128

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.000171

Hom.:

Bravo

AF:

0.00285

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00162

AC:

197

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PDGFRA p.Leu786Arg variant was identified in dbSNP (ID: rs148654387) and ClinVar (classified as benign by Invitae in 2018) but was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 581 of 282518 chromosomes (8 homozygous) at a frequency of 0.002057 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 563 of 35410 chromosomes (freq: 0.0159), Other in 13 of 7208 chromosomes (freq: 0.001804), African in 2 of 24974 chromosomes (freq: 0.00008), South Asian in 2 of 30604 chromosomes (freq: 0.000065) and European (non-Finnish) in 1 of 128928 chromosomes (freq: 0.000008); it was not observed in the Ashkenazi Jewish, East Asian, and European (Finnish) populations. The p.Leu786Arg variant was identified in a cohort of 681 healthy adults at allele frequency 0.0029 (0.0169 among Hispanic adults) (Bodian_2014_PMID: 24728327). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Leu786 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Gastrointestinal stromal tumor

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2018

This alteration is classified as 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. -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

.;T

Eigen

Benign

-0.095

Eigen_PC

Benign

-0.0050

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;D

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.93

.;L

MutationTaster

Benign

1.0

N;D

PrimateAI

Benign

0.40

PROVEAN

Benign

0.87

N;N

REVEL

Uncertain

0.38

Sift

Benign

0.46

T;T

Sift4G

Benign

0.43

T;T

Polyphen

0.55

.;P

Vest4

0.53

MVP

0.68

MPC

1.0

ClinPred

0.058

GERP RS

4.6

Varity_R

0.22

gMVP

0.63

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over