Genetic Variant PF4:p.Glu59Lys (chr4-73981460-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002619.4(PF4):c.175G>A(p.Glu59Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E59Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PF4
NM_002619.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.434

Publications

0 publications found

Variant links:

Genes affected

PF4 (HGNC:8861): (platelet factor 4) This gene encodes a member of the CXC chemokine family. This chemokine is released from the alpha granules of activated platelets in the form of a homotetramer which has high affinity for heparin and is involved in platelet aggregation. This protein is chemotactic for numerous other cell type and also functions as an inhibitor of hematopoiesis, angiogenesis and T-cell function. The protein also exhibits antimicrobial activity against Plasmodium falciparum. [provided by RefSeq, Oct 2014]

PF4 links:

ENSG00000288796 (HGNC:):

ENSG00000288796 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002619.4. 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
	PF4	NM_002619.4	MANE Select	c.175G>A	p.Glu59Lys	missense	Exon 2 of 3	NP_002610.1	P02776
	PF4	NM_001363352.1		c.202G>A	p.Glu68Lys	missense	Exon 2 of 3	NP_001350281.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PF4	ENST00000296029.4	TSL:1 MANE Select	c.175G>A	p.Glu59Lys	missense	Exon 2 of 3	ENSP00000296029.3	P02776
ENSG00000288796	ENST00000693342.1		c.451G>A	p.Glu151Lys	missense	Exon 4 of 5	ENSP00000510492.1	A0A8I5KW61
PF4	ENST00000687529.1		n.*206G>A		non_coding_transcript_exon	Exon 2 of 3	ENSP00000508485.1	A0A8I5QJ57

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000568638), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.82

M_CAP

Benign

0.0025

MetaRNN

Benign

0.40

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

0.43

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.060

Sift

Benign

0.20

Sift4G

Benign

0.32

Polyphen

0.91

Vest4

0.42

MutPred

0.44

Gain of methylation at E59 (P = 0.0101)

MVP

0.51

MPC

0.53

ClinPred

0.97

GERP RS

0.80

Varity_R

0.53

gMVP

0.42

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.28

Position offset: -2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over