rs3690

Positions:

• chr4-54295646-A-C
• chr4-54295646-A-G
• chr4-54295646-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006206.6(PDGFRA):​c.*374A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 371,152 control chromosomes in the GnomAD database, including 6,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3651 hom., cov: 32)
  • Exomes 𝑓: 0.15 (2793 hom.)
• Consequence: PDGFRA NM_006206.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.14

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 4-54295646-A-C is Benign according to our data. Variant chr4-54295646-A-C is described in ClinVar as [Benign]. Clinvar id is 348916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDGFRA	NM_006206.6	c.*374A>C		3_prime_UTR_variant	23/23	ENST00000257290.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDGFRA	ENST00000257290.10	c.*374A>C		3_prime_UTR_variant	23/23	1	NM_006206.6	P1

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30383 AN: 151996 Hom.: 3653 Cov.: 32

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.0680

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.168

GnomAD4 exome AF: 0.149 AC: 32563 AN: 219038 Hom.: 2793 Cov.: 0 AF XY: 0.151 AC XY: 16553 AN XY: 109618

Gnomad4 AFR exome AF: 0.315

Gnomad4 AMR exome AF: 0.262

Gnomad4 ASJ exome AF: 0.0787

Gnomad4 EAS exome AF: 0.140

Gnomad4 SAS exome AF: 0.197

Gnomad4 FIN exome AF: 0.117

Gnomad4 NFE exome AF: 0.132

Gnomad4 OTH exome AF: 0.144

GnomAD4 genome AF: 0.200 AC: 30394 AN: 152114 Hom.: 3651 Cov.: 32 AF XY: 0.200 AC XY: 14900 AN XY: 74388

Gnomad4 AFR AF: 0.322

Gnomad4 AMR AF: 0.240

Gnomad4 ASJ AF: 0.0680

Gnomad4 EAS AF: 0.143

Gnomad4 SAS AF: 0.238

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.166

Alfa AF: 0.134 Hom.: 859

Bravo AF: 0.213

Asia WGS AF: 0.209 AC: 727 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Idiopathic hypereosinophilic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Gastrointestinal stromal tumor Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	11
DANN	Benign	0.73

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: rs3690; hg19: chr4-55161813;