NM_006206.6:c.-13+12G>T

Variant names:

• chr4-54229427-G-T
• rs760170961
• NM_006206.6:c.-13+12G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006206.6(PDGFRA):​c.-13+12G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000358 in 397,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: PDGFRA NM_006206.6 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.815

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]

ENSG00000282278 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BS2: High AC in GnomAd4 at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDGFRA	NM_006206.6	c.-13+12G>T		intron_variant	Intron 1 of 22	ENST00000257290.10	NP_006197.1
PDGFRA	NM_001347828.2	c.-16+12G>T		intron_variant	Intron 1 of 23		NP_001334757.1
PDGFRA	NM_001347827.2	c.-13+12G>T		intron_variant	Intron 1 of 16		NP_001334756.1
PDGFRA	XM_006714041.4	c.-16+12G>T		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	c.-13+12G>T		intron_variant	Intron 1 of 22	1	NM_006206.6	ENSP00000257290.5
ENSG00000282278	ENST00000507166.5	c.1018-45498G>T		intron_variant	Intron 12 of 23	2		ENSP00000423325.1

Frequencies

GnomAD3 genomes AF: 0.000297 AC: 45 AN: 151310 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000589

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000395 AC: 97 AN: 245658 Hom.: 0 Cov.: 0 AF XY: 0.000361 AC XY: 45 AN XY: 124496

African (AFR) AF: 0.000420 AC: 3 AN: 7144

American (AMR) AF: 0.00 AC: 0 AN: 7408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9224

East Asian (EAS) AF: 0.00 AC: 0 AN: 22854

South Asian (SAS) AF: 0.00 AC: 0 AN: 3018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20744

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1286

European-Non Finnish (NFE) AF: 0.000520 AC: 82 AN: 157632

Other (OTH) AF: 0.000734 AC: 12 AN: 16348

GnomAD4 genome AF: 0.000297 AC: 45 AN: 151430 Hom.: 0 Cov.: 32 AF XY: 0.000284 AC XY: 21 AN XY: 73988

African (AFR) AF: 0.000121 AC: 5 AN: 41278

American (AMR) AF: 0.00 AC: 0 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000589 AC: 40 AN: 67860

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000409 Hom.: 0

Bravo AF: 0.000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Idiopathic hypereosinophilic syndrome Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Gastrointestinal stromal tumor Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	15
DANN	Benign	0.83
PhyloP100		0.81
PromoterAI		-0.0068	Neutral
Mutation Taster		=100/0	polymorphism

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

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Other links and lift over

dbSNP: rs760170961; hg19: chr4-55095594; COSMIC: COSV107229703;