NM_006206.6:c.201C>T

Variant names:

• chr4-54261246-C-T
• rs35805947
• NM_006206.6:c.201C>T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006206.6(PDGFRA):​c.201C>T​(p.Ser67Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00335 in 1,614,014 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0033 (4 hom.)
• Consequence: PDGFRA NM_006206.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0990

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]

ENSG00000282278 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 4-54261246-C-T is Benign according to our data. Variant chr4-54261246-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 240322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54261246-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.099 with no splicing effect.
• BS2: High AC in GnomAd4 at 617 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDGFRA	NM_006206.6	c.201C>T	p.Ser67Ser	synonymous_variant	Exon 3 of 23	ENST00000257290.10	NP_006197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDGFRA	ENST00000257290.10	c.201C>T	p.Ser67Ser	synonymous_variant	Exon 3 of 23	1	NM_006206.6	ENSP00000257290.5
ENSG00000282278	ENST00000507166.5	c.1018-13679C>T		intron_variant	Intron 12 of 23	2		ENSP00000423325.1

Frequencies

GnomAD3 genomes AF: 0.00407 AC: 618 AN: 152028 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00720

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00840

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00310

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00298 AC: 750 AN: 251376 Hom.: 3 AF XY: 0.00280 AC XY: 380 AN XY: 135858

Gnomad AFR exome AF: 0.00824

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00882

Gnomad NFE exome AF: 0.00321

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00328 AC: 4789 AN: 1461868 Hom.: 4 Cov.: 32 AF XY: 0.00318 AC XY: 2310 AN XY: 727238

Gnomad4 AFR exome AF: 0.00854

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.000612

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00878

Gnomad4 NFE exome AF: 0.00339

Gnomad4 OTH exome AF: 0.00311

GnomAD4 genome AF: 0.00406 AC: 617 AN: 152146 Hom.: 1 Cov.: 31 AF XY: 0.00384 AC XY: 286 AN XY: 74388

Gnomad4 AFR AF: 0.00716

Gnomad4 AMR AF: 0.000655

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00840

Gnomad4 NFE AF: 0.00310

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00362 Hom.: 0

Bravo AF: 0.00399

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00196

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Apr 19, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PDGFRA: BP4, BP7 -

Gastrointestinal stromal tumor Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Hereditary cancer-predisposing syndrome Benign:2

Sep 27, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Oct 22, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not specified Benign:1

Sep 13, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Idiopathic hypereosinophilic syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.77
CADD	Benign	8.1
DANN	Benign	0.62

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: rs35805947; hg19: chr4-55127413; COSMIC: COSV104566398;