4-54273604-T-C

Position:

• chr4-54273604-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The ENST00000257290.10(PDGFRA):​c.1432T>C​(p.Ser478Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,613,404 control chromosomes in the GnomAD database, including 14,579 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S478F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.15 (2161 hom., cov: 31)
  • Exomes 𝑓: 0.12 (12418 hom.)
• Consequence: PDGFRA ENST00000257290.10 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:8 O:1
• Conservation: PhyloP100: -1.15

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 -19 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=0.0077081323).
• BP6: Variant 4-54273604-T-C is Benign according to our data. Variant chr4-54273604-T-C is described in ClinVar as [Benign]. Clinvar id is 41794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDGFRA	NM_006206.6	c.1432T>C	p.Ser478Pro	missense_variant	10/23	ENST00000257290.10	NP_006197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDGFRA	ENST00000257290.10	c.1432T>C	p.Ser478Pro	missense_variant	10/23	1	NM_006206.6	ENSP00000257290	P1
PDGFRA	ENST00000509092.5	n.1250T>C		non_coding_transcript_exon_variant	9/15	1
PDGFRA	ENST00000509490.5	c.1432T>C	p.Ser478Pro	missense_variant, NMD_transcript_variant	10/18	1		ENSP00000424218

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23418 AN: 151798 Hom.: 2161 Cov.: 31

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.0562

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.127

GnomAD3 exomes AF: 0.154 AC: 38733 AN: 251048 Hom.: 3673 AF XY: 0.150 AC XY: 20316 AN XY: 135690

Gnomad AFR exome AF: 0.236

Gnomad AMR exome AF: 0.285

Gnomad ASJ exome AF: 0.0579

Gnomad EAS exome AF: 0.143

Gnomad SAS exome AF: 0.208

Gnomad FIN exome AF: 0.123

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.122 AC: 177975 AN: 1461488 Hom.: 12418 Cov.: 33 AF XY: 0.122 AC XY: 89046 AN XY: 727074

Gnomad4 AFR exome AF: 0.230

Gnomad4 AMR exome AF: 0.275

Gnomad4 ASJ exome AF: 0.0629

Gnomad4 EAS exome AF: 0.142

Gnomad4 SAS exome AF: 0.205

Gnomad4 FIN exome AF: 0.121

Gnomad4 NFE exome AF: 0.107

Gnomad4 OTH exome AF: 0.120

GnomAD4 genome AF: 0.154 AC: 23436 AN: 151916 Hom.: 2161 Cov.: 31 AF XY: 0.157 AC XY: 11659 AN XY: 74258

Gnomad4 AFR AF: 0.229

Gnomad4 AMR AF: 0.202

Gnomad4 ASJ AF: 0.0562

Gnomad4 EAS AF: 0.143

Gnomad4 SAS AF: 0.228

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.105

Gnomad4 OTH AF: 0.126

Alfa AF: 0.120 Hom.: 1307

Bravo AF: 0.163

TwinsUK AF: 0.111 AC: 413

ALSPAC AF: 0.109 AC: 420

ESP6500AA AF: 0.226 AC: 995

ESP6500EA AF: 0.103 AC: 882

ExAC AF: 0.151 AC: 18396

Asia WGS AF: 0.210 AC: 729 AN: 3478

EpiCase AF: 0.100

EpiControl AF: 0.0983

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

Gastrointestinal stromal tumor Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Myeloproliferative neoplasm, unclassifiable Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Dept. of Cytogenetics, ICMR- National Institute of Immunohaematology

Aug 25, 2022

- -

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. -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	1.0
DANN	Benign	0.66
DEOGEN2	Benign	0.080	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0070	N
LIST_S2	Benign	0.071	T
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.088
Sift	Benign	0.30	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.065
MPC		0.41
ClinPred		0.0012	T
GERP RS		0.81
Varity_R		0.078
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

Other links and lift over

dbSNP: rs35597368; hg19: chr4-55139771; COSMIC: COSV57266881; COSMIC: COSV57266881;