Genetic Variant PDGFRA:c.-13+110_-13+111dupAA (chr4-54229515-G-GAA) – 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+110_-13+111dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00666 in 321,666 control chromosomes in the GnomAD database, including 9 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0061 ( 9 hom., cov: 21)

Exomes 𝑓: 0.0071 ( 0 hom. )

Consequence

PDGFRA
NM_006206.6 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.51

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 afr. GnomAdExome4 allele frequency = 0.00714 (1281/179320) while in subpopulation AFR AF = 0.024 (131/5464). AF 95% confidence interval is 0.0206. There are 0 homozygotes in GnomAdExome4. There are 627 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

BS2

High AC in GnomAd4 at 862 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PDGFRA	NM_006206.6 link	c.-13+110_-13+111dupAA	intron_variant	Intron 1 of 22	ENST00000257290.10	NP_006197.1	P16234-1
PDGFRA	NM_001347828.2 link	c.-16+110_-16+111dupAA	intron_variant	Intron 1 of 23		NP_001334757.1
PDGFRA	NM_001347827.2 link	c.-13+110_-13+111dupAA	intron_variant	Intron 1 of 16		NP_001334756.1
PDGFRA	XM_006714041.4 link	c.-16+110_-16+111dupAA	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+110_-13+111dupAA		intron_variant	Intron 1 of 22	1	NM_006206.6	ENSP00000257290.5		P16234-1
ENSG00000282278	ENST00000507166.5 link	c.1018-45400_1018-45399dupAA		intron_variant	Intron 12 of 23	2		ENSP00000423325.1		A0A0B4J203

Frequencies

GnomAD3 genomes

AF:

0.00604

AC:

860

AN:

142300

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00507

Gnomad ASJ

AF:

0.00151

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000443

Gnomad FIN

AF:

0.00183

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00291

Gnomad OTH

AF:

0.00512

GnomAD4 exome

AF:

0.00714

AC:

1281

AN:

179320

Hom.:

AF XY:

0.00688

AC XY:

627

AN XY:

91068

show subpopulations

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

African (AFR)

AF:

0.0240

AC:

131

AN:

5464

American (AMR)

AF:

0.0127

AC:

AN:

5650

Ashkenazi Jewish (ASJ)

AF:

0.00332

AC:

AN:

6322

East Asian (EAS)

AF:

0.00310

AC:

AN:

16444

South Asian (SAS)

AF:

0.00481

AC:

AN:

1662

European-Finnish (FIN)

AF:

0.00489

AC:

AN:

14736

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

882

European-Non Finnish (NFE)

AF:

0.00700

AC:

812

AN:

116044

Other (OTH)

AF:

0.00891

AC:

108

AN:

12116

⚠️ 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: 0.316

Heterozygous variant carriers

173

260

346

433

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00606

AC:

862

AN:

142346

Hom.:

Cov.:

AF XY:

0.00625

AC XY:

431

AN XY:

68944

show subpopulations

African (AFR)

AF:

0.0146

AC:

569

AN:

39070

American (AMR)

AF:

0.00507

AC:

AN:

14408

Ashkenazi Jewish (ASJ)

AF:

0.00151

AC:

AN:

3320

East Asian (EAS)

AF:

0.00

AC:

AN:

4886

South Asian (SAS)

AF:

0.000445

AC:

AN:

4490

European-Finnish (FIN)

AF:

0.00183

AC:

AN:

8186

Middle Eastern (MID)

AF:

0.00

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.00290

AC:

188

AN:

64870

Other (OTH)

AF:

0.00509

AC:

AN:

1966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

109

146

182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000909

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.5

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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4-54229515-GAAA-GAAAAA

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