4-54229515-GAAA-GAAAAA

Variant names:

• chr4-54229515-G-GAA
• rs565335773
• NM_006206.6:c.-13+110_-13+111dupAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.51
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• gastrointestinal stromal tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• polyps, multiple and recurrent inflammatory fibroid, gastrointestinal

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• isolated cleft palate

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000282278 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 862 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006206.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDGFRA	NM_006206.6	MANE Select	c.-13+110_-13+111dupAA		intron	N/A	NP_006197.1	P16234-1
	PDGFRA	NM_001347828.2		c.-16+110_-16+111dupAA		intron	N/A	NP_001334757.1
	PDGFRA	NM_001347827.2		c.-13+110_-13+111dupAA		intron	N/A	NP_001334756.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDGFRA	ENST00000257290.10	TSL:1 MANE Select	c.-13+100_-13+101insAA		intron	N/A	ENSP00000257290.5	P16234-1
	ENSG00000282278	ENST00000507166.5	TSL:2	c.1018-45410_1018-45409insAA		intron	N/A	ENSP00000423325.1	A0A0B4J203
	PDGFRA	ENST00000508170.5	TSL:1	c.-13+100_-13+101insAA		intron	N/A	ENSP00000425648.1	P16234-2

Frequencies

GnomAD3 genomes AF: 0.00604 AC: 860 AN: 142300 Hom.: 9 Cov.: 21

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.: 0 AF XY: 0.00688 AC XY: 627 AN XY: 91068

⚠️ 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: 72 AN: 5650

Ashkenazi Jewish (ASJ) AF: 0.00332 AC: 21 AN: 6322

East Asian (EAS) AF: 0.00310 AC: 51 AN: 16444

South Asian (SAS) AF: 0.00481 AC: 8 AN: 1662

European-Finnish (FIN) AF: 0.00489 AC: 72 AN: 14736

Middle Eastern (MID) AF: 0.00680 AC: 6 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), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00606 AC: 862 AN: 142346 Hom.: 9 Cov.: 21 AF XY: 0.00625 AC XY: 431 AN XY: 68944

African (AFR) AF: 0.0146 AC: 569 AN: 39070

American (AMR) AF: 0.00507 AC: 73 AN: 14408

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 5 AN: 3320

East Asian (EAS) AF: 0.00 AC: 0 AN: 4886

South Asian (SAS) AF: 0.000445 AC: 2 AN: 4490

European-Finnish (FIN) AF: 0.00183 AC: 15 AN: 8186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.00290 AC: 188 AN: 64870

Other (OTH) AF: 0.00509 AC: 10 AN: 1966

Alfa AF: 0.000909 Hom.: 67

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs565335773; hg19: chr4-55095682;