rs5939

Variant names:

• chr1-28150009-T-C
• rs5939
• NM_000952.5:c.1013A>G

Variant summary

Our verdict is Benign. The variant received -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. 16/22 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 the same amino acid substitution has been previously reported as Likely benign in 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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PTAFR	NM_000952.5	c.1013A>G	p.Asn338Ser	missense_variant	Exon 2 of 2	ENST00000373857.8	NP_000943.1
PTAFR	NM_001164721.2	c.1013A>G	p.Asn338Ser	missense_variant	Exon 3 of 3		NP_001158193.1
PTAFR	NM_001164722.3	c.1013A>G	p.Asn338Ser	missense_variant	Exon 2 of 2		NP_001158194.1
PTAFR	NM_001164723.3	c.1013A>G	p.Asn338Ser	missense_variant	Exon 3 of 3		NP_001158195.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTAFR	ENST00000373857.8	c.1013A>G	p.Asn338Ser	missense_variant	Exon 2 of 2	1	NM_000952.5	ENSP00000362965.3
PTAFR	ENST00000305392.3	c.1013A>G	p.Asn338Ser	missense_variant	Exon 2 of 2	1		ENSP00000301974.3
PTAFR	ENST00000539896.1	c.1013A>G	p.Asn338Ser	missense_variant	Exon 3 of 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

GnomAD2 exomes AF: 0.00615 AC: 1538 AN: 250060 AF XY: 0.00469

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 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 AC: 2499 AN: 33438

Gnomad4 AMR exome AF: 0.00558 AC: 249 AN: 44618

Gnomad4 ASJ exome AF: 0.000231 AC: 6 AN: 26028

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39686

Gnomad4 SAS exome AF: 0.000105 AC: 9 AN: 86108

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53366

Gnomad4 NFE exome AF: 0.000530 AC: 589 AN: 1110764

Gnomad4 Remaining exome AF: 0.00535 AC: 323 AN: 60332

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 AC: 0.073438 AN: 0.073438

Gnomad4 AMR AF: 0.0107 AC: 0.0107288 AN: 0.0107288

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000416 AC: 0.000415628 AN: 0.000415628

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000353 AC: 0.000352889 AN: 0.000352889

Gnomad4 OTH AF: 0.0199 AC: 0.019943 AN: 0.019943

Alfa AF: 0.00796 Hom.: 85

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
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

Publications

LitVar

Other links and lift over

dbSNP: rs5939; hg19: chr1-28476520;