chr4-54274888-A-G

Position:

chr4-54274888-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006206.6(PDGFRA):c.1701A>G(p.Pro567Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.993 in 1,613,940 control chromosomes in the GnomAD database, including 795,435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.97 ( 71320 hom., cov: 31)

Exomes 𝑓: 1.0 ( 724115 hom. )

Consequence

PDGFRA
NM_006206.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -3.56

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:

ENSG00000282278 (HGNC:):

ENSG00000282278 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BP6

Variant 4-54274888-A-G is Benign according to our data. Variant chr4-54274888-A-G is described in ClinVar as [Benign]. Clinvar id is 259949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54274888-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.56 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDGFRA	NM_006206.6 linkuse as main transcript	c.1701A>G	p.Pro567Pro	synonymous_variant	12/23	ENST00000257290.10	NP_006197.1	P16234-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PDGFRA	ENST00000257290.10 linkuse as main transcript	c.1701A>G	p.Pro567Pro	synonymous_variant	12/23	1	NM_006206.6	ENSP00000257290.5	P16234-1
ENSG00000282278	ENST00000507166.5 linkuse as main transcript	c.1018-37A>G		intron_variant		2		ENSP00000423325.1	A0A0B4J203
PDGFRA	ENST00000509092.5 linkuse as main transcript	n.1519A>G		non_coding_transcript_exon_variant	11/15	1
PDGFRA	ENST00000509490.5 linkuse as main transcript	n.1701A>G		non_coding_transcript_exon_variant	12/18	1		ENSP00000424218.1	P16234-3

Frequencies

GnomAD3 genomes

AF:

0.967

AC:

147117

AN:

152124

Hom.:

71292

Cov.:

show subpopulations

Gnomad AFR

AF:

0.890

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.985

Gnomad ASJ

AF:

0.993

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.999

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.981

Gnomad NFE

AF:

0.998

Gnomad OTH

AF:

0.971

GnomAD3 exomes

AF:

0.990

AC:

248680

AN:

251180

Hom.:

123190

AF XY:

0.992

AC XY:

134683

AN XY:

135728

show subpopulations

Gnomad AFR exome

AF:

0.885

Gnomad AMR exome

AF:

0.991

Gnomad ASJ exome

AF:

0.994

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

0.998

Gnomad OTH exome

AF:

0.992

GnomAD4 exome

AF:

0.995

AC:

1454661

AN:

1461698

Hom.:

724115

Cov.:

AF XY:

0.996

AC XY:

723988

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.877

Gnomad4 AMR exome

AF:

0.990

Gnomad4 ASJ exome

AF:

0.993

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.999

Gnomad4 FIN exome

AF:

1.00

Gnomad4 NFE exome

AF:

0.999

Gnomad4 OTH exome

AF:

0.988

GnomAD4 genome

AF:

0.967

AC:

147194

AN:

152242

Hom.:

71320

Cov.:

AF XY:

0.968

AC XY:

72095

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.889

Gnomad4 AMR

AF:

0.985

Gnomad4 ASJ

AF:

0.993

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

0.999

Gnomad4 FIN

AF:

1.00

Gnomad4 NFE

AF:

0.998

Gnomad4 OTH

AF:

0.971

Alfa

AF:

0.985

Hom.:

49237

Bravo

AF:

0.961

Asia WGS

AF:

0.986

AC:

3430

AN:

3478

EpiCase

AF:

0.998

EpiControl

AF:

0.998

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -

Gastrointestinal stromal tumor

Benign:2

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

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. -

Carcinoma of colon

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

This variant was identified in the 1000 Genomes Project in 80 of 2162 chromosomes (frequency: 0.037), Exome Variant Server project in 8587 of 9122 European American and in 3884 of 4406 African American alleles, increasing the likelihood that this is/may be a low frequency benign variant in certain populations of origin. The p.Pro567Pro variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site.In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Squamous cell lung carcinoma

Benign:1

Likely benign, no assertion criteria provided

clinical testing;in vivo

Faculté Pluridciplinaire Nador, Université Mohamed Premier

May 05, 2020

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.093

DANN

Benign

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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