Genetic Variant PDGFRA:c.-13+156delT (chr4-54229560-AT-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_006206.6(PDGFRA):c.-13+156delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 314,760 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.023 ( 0 hom. )

Consequence

PDGFRA
NM_006206.6 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.284

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0233 (3865/166018) while in subpopulation MID AF = 0.0267 (23/862). AF 95% confidence interval is 0.0228. There are 0 homozygotes in GnomAdExome4. There are 1960 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

BS2

High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PDGFRA	NM_006206.6 link	c.-13+156delT	intron_variant	Intron 1 of 22	ENST00000257290.10	NP_006197.1	P16234-1
PDGFRA	NM_001347828.2 link	c.-16+156delT	intron_variant	Intron 1 of 23		NP_001334757.1
PDGFRA	NM_001347827.2 link	c.-13+156delT	intron_variant	Intron 1 of 16		NP_001334756.1
PDGFRA	XM_006714041.4 link	c.-16+156delT	intron_variant	Intron 1 of 17		XP_006714104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDGFRA	ENST00000257290.10 link	c.-13+156delT		intron_variant	Intron 1 of 22	1	NM_006206.6	ENSP00000257290.5		P16234-1
ENSG00000282278	ENST00000507166.5 link	c.1018-45354delT		intron_variant	Intron 12 of 23	2		ENSP00000423325.1		A0A0B4J203

Frequencies

GnomAD3 genomes

AF:

0.000135

AC:

AN:

148680

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000197

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000672

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000514

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000896

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0233

AC:

3865

AN:

166018

Hom.:

AF XY:

0.0233

AC XY:

1960

AN XY:

84040

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0247

AC:

122

AN:

4942

American (AMR)

AF:

0.0200

AC:

101

AN:

5040

Ashkenazi Jewish (ASJ)

AF:

0.0224

AC:

136

AN:

6072

East Asian (EAS)

AF:

0.0242

AC:

384

AN:

15856

South Asian (SAS)

AF:

0.0170

AC:

AN:

1468

European-Finnish (FIN)

AF:

0.0222

AC:

318

AN:

14296

Middle Eastern (MID)

AF:

0.0267

AC:

AN:

862

European-Non Finnish (NFE)

AF:

0.0235

AC:

2506

AN:

106448

Other (OTH)

AF:

0.0227

AC:

250

AN:

11034

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.247

Heterozygous variant carriers

567

1135

1702

2270

2837

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000134

AC:

AN:

148742

Hom.:

Cov.:

AF XY:

0.0000552

AC XY:

AN XY:

72480

show subpopulations

African (AFR)

AF:

0.000197

AC:

AN:

40678

American (AMR)

AF:

0.0000671

AC:

AN:

14898

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3432

East Asian (EAS)

AF:

0.00

AC:

AN:

5112

South Asian (SAS)

AF:

0.00

AC:

AN:

4698

European-Finnish (FIN)

AF:

0.000514

AC:

AN:

9728

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0000896

AC:

AN:

66964

Other (OTH)

AF:

0.00

AC:

AN:

2042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.412

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.28

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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4-54229560-ATT-AT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over