rs36035373

Positions:

• chr4-54261281-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_006206.6(PDGFRA):​c.236G>A​(p.Gly79Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,614,138 control chromosomes in the GnomAD database, including 152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G79S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0087 (9 hom., cov: 31)
  • Exomes 𝑓: 0.013 (143 hom.)
• Consequence: PDGFRA NM_006206.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 7.65

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 Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PDGFRA
• BP4: Computational evidence support a benign effect (MetaRNN=0.0074451566).
• BP6: Variant 4-54261281-G-A is Benign according to our data. Variant chr4-54261281-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 41797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54261281-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 1325 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDGFRA	NM_006206.6	c.236G>A	p.Gly79Asp	missense_variant	3/23	ENST00000257290.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDGFRA	ENST00000257290.10	c.236G>A	p.Gly79Asp	missense_variant	3/23	1	NM_006206.6	P1

Frequencies

GnomAD3 genomes AF: 0.00871 AC: 1325 AN: 152154 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.0137

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00888 AC: 2233 AN: 251366 Hom.: 16 AF XY: 0.00935 AC XY: 1270 AN XY: 135850

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00228

Gnomad ASJ exome AF: 0.0126

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00353

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0127 AC: 18505 AN: 1461866 Hom.: 143 Cov.: 32 AF XY: 0.0126 AC XY: 9141 AN XY: 727232

Gnomad4 AFR exome AF: 0.00194

Gnomad4 AMR exome AF: 0.00259

Gnomad4 ASJ exome AF: 0.0121

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00356

Gnomad4 FIN exome AF: 0.0134

Gnomad4 NFE exome AF: 0.0147

Gnomad4 OTH exome AF: 0.0103

GnomAD4 genome AF: 0.00870 AC: 1325 AN: 152272 Hom.: 9 Cov.: 31 AF XY: 0.00834 AC XY: 621 AN XY: 74460

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.0137

Gnomad4 NFE AF: 0.0141

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.0130 Hom.: 6

Bravo AF: 0.00763

TwinsUK AF: 0.0132 AC: 49

ALSPAC AF: 0.0143 AC: 55

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0137 AC: 118

ExAC AF: 0.00875 AC: 1062

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0150

EpiControl AF: 0.0130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PDGFRA: BS1, BS2 -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2019	This variant is associated with the following publications: (PMID: 28192086, 19755855, 24728327, 22703879, 17344846, 29205322) -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 11, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 26, 2019	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. -
Likely benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Jan 29, 2016	- -

Gastrointestinal stromal tumor Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Idiopathic hypereosinophilic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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	Pathogenic	0.79
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.;T;.;.;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
MetaRNN	Benign	0.0074	T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.2	M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0060	D;D;D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D;D;D
Polyphen		0.99	D;D;.;.;.;.
Vest4		0.87
MVP		0.42
MPC		1.2
ClinPred		0.018	T
GERP RS		6.0
Varity_R		0.37
gMVP		0.88

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: rs36035373; hg19: chr4-55127448; COSMIC: COSV57267390;