rs3690

Variant names:

• chr4-54295646-A-C
• rs3690
• NM_006206.6:c.*374A>C

Your query was ambiguous. Multiple possible variants found:

• chr4-54295646-A-C
• chr4-54295646-A-G
• chr4-54295646-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006206.6(PDGFRA):​c.*374A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 371,152 control chromosomes in the GnomAD database, including 6,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3651 hom., cov: 32)
  • Exomes 𝑓: 0.15 (2793 hom.)
• Consequence: PDGFRA NM_006206.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.14
• Publications: 17 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: Genomics England PanelApp, Ambry Genetics, G2P
• congenital heart disease

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

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 4-54295646-A-C is Benign according to our data. Variant chr4-54295646-A-C is described in ClinVar as Benign. ClinVar VariationId is 348916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDGFRA	NM_006206.6	c.*374A>C		3_prime_UTR_variant	Exon 23 of 23	ENST00000257290.10	NP_006197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDGFRA	ENST00000257290.10	c.*374A>C		3_prime_UTR_variant	Exon 23 of 23	1	NM_006206.6	ENSP00000257290.5

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30383 AN: 151996 Hom.: 3653 Cov.: 32

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.0680

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.168

GnomAD4 exome AF: 0.149 AC: 32563 AN: 219038 Hom.: 2793 Cov.: 0 AF XY: 0.151 AC XY: 16553 AN XY: 109618

African (AFR) AF: 0.315 AC: 2615 AN: 8310

American (AMR) AF: 0.262 AC: 2163 AN: 8248

Ashkenazi Jewish (ASJ) AF: 0.0787 AC: 686 AN: 8720

East Asian (EAS) AF: 0.140 AC: 2489 AN: 17838

South Asian (SAS) AF: 0.197 AC: 4271 AN: 21666

European-Finnish (FIN) AF: 0.117 AC: 847 AN: 7218

Middle Eastern (MID) AF: 0.0988 AC: 101 AN: 1022

European-Non Finnish (NFE) AF: 0.132 AC: 17370 AN: 131972

Other (OTH) AF: 0.144 AC: 2021 AN: 14044

GnomAD4 genome AF: 0.200 AC: 30394 AN: 152114 Hom.: 3651 Cov.: 32 AF XY: 0.200 AC XY: 14900 AN XY: 74388

African (AFR) AF: 0.322 AC: 13362 AN: 41448

American (AMR) AF: 0.240 AC: 3672 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0680 AC: 236 AN: 3470

East Asian (EAS) AF: 0.143 AC: 741 AN: 5182

South Asian (SAS) AF: 0.238 AC: 1147 AN: 4812

European-Finnish (FIN) AF: 0.130 AC: 1380 AN: 10594

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9366 AN: 68004

Other (OTH) AF: 0.166 AC: 351 AN: 2116

Alfa AF: 0.147 Hom.: 1701

Bravo AF: 0.213

Asia WGS AF: 0.209 AC: 727 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 13, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Idiopathic hypereosinophilic syndrome Benign:1

Jan 12, 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. -

Gastrointestinal stromal tumor Benign:1

Jan 12, 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	-0.58
CADD	Benign	11
DANN	Benign	0.73
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3690; hg19: chr4-55161813;