rs5939

Positions:

• chr1-28150009-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000952.5(PTAFR):​c.1013A>G​(p.Asn338Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00434 in 1,612,284 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N338D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (115 hom., cov: 31)
  • Exomes 𝑓: 0.0025 (115 hom.)
• Consequence: PTAFR NM_000952.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.351

Genes affected

PTAFR (HGNC:9582): (platelet activating factor receptor) This gene encodes a seven-transmembrane G-protein-coupled receptor for platelet-activating factor (PAF) that localizes to lipid rafts and/or caveolae in the cell membrane. PAF (1-0-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine) is a phospholipid that plays a significant role in oncogenic transformation, tumor growth, angiogenesis, metastasis, and pro-inflammatory processes. Binding of PAF to the PAF-receptor (PAFR) stimulates numerous signal transduction pathways including phospholipase C, D, A2, mitogen-activated protein kinases (MAPKs), and the phosphatidylinositol-calcium second messenger system. Following PAFR activation, cells become rapidly desensitized and this refractory state is dependent on PAFR phosphorylation, internalization, and down-regulation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002279222).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0713 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTAFR	NM_000952.5	c.1013A>G	p.Asn338Ser	missense_variant	2/2	ENST00000373857.8	NP_000943.1
PTAFR	NM_001164721.2	c.1013A>G	p.Asn338Ser	missense_variant	3/3		NP_001158193.1
PTAFR	NM_001164722.3	c.1013A>G	p.Asn338Ser	missense_variant	2/2		NP_001158194.1
PTAFR	NM_001164723.3	c.1013A>G	p.Asn338Ser	missense_variant	3/3		NP_001158195.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTAFR	ENST00000373857.8	c.1013A>G	p.Asn338Ser	missense_variant	2/2	1	NM_000952.5	ENSP00000362965.3
PTAFR	ENST00000305392.3	c.1013A>G	p.Asn338Ser	missense_variant	2/2	1		ENSP00000301974.3
PTAFR	ENST00000539896.1	c.1013A>G	p.Asn338Ser	missense_variant	3/3	2		ENSP00000442658.1

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3274 AN: 152074 Hom.: 115 Cov.: 31

Gnomad AFR AF: 0.0733

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0202

GnomAD3 exomes AF: 0.00615 AC: 1538 AN: 250060 Hom.: 65 AF XY: 0.00469 AC XY: 634 AN XY: 135120

Gnomad AFR exome AF: 0.0794

Gnomad AMR exome AF: 0.00482

Gnomad ASJ exome AF: 0.000302

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000656

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000505

Gnomad OTH exome AF: 0.00328

GnomAD4 exome AF: 0.00254 AC: 3714 AN: 1460092 Hom.: 115 Cov.: 31 AF XY: 0.00222 AC XY: 1614 AN XY: 726178

Gnomad4 AFR exome AF: 0.0747

Gnomad4 AMR exome AF: 0.00558

Gnomad4 ASJ exome AF: 0.000231

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000530

Gnomad4 OTH exome AF: 0.00535

GnomAD4 genome AF: 0.0216 AC: 3286 AN: 152192 Hom.: 115 Cov.: 31 AF XY: 0.0207 AC XY: 1539 AN XY: 74404

Gnomad4 AFR AF: 0.0734

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.00476 Hom.: 30

Bravo AF: 0.0247

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0735 AC: 324

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00741 AC: 899

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.028
DANN	Benign	0.27
DEOGEN2	Benign	0.044	T;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.24	.;T;.
MetaRNN	Benign	0.0023	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.090	N;N;N
REVEL	Benign	0.060
Sift	Benign	0.72	T;T;T
Sift4G	Benign	0.51	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.059
MVP		0.53
MPC		0.38
ClinPred		0.00016	T
GERP RS		-1.5
Varity_R		0.021
gMVP		0.13

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

Publications

LitVar

Other links and lift over

dbSNP: rs5939; hg19: chr1-28476520;