4-73987334-C-T

Variant names:

• chr4-73987334-C-T
• rs1446904093
• NM_002704.3:c.325G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002704.3(PPBP):​c.325G>A​(p.Asp109Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PPBP NM_002704.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.667

Genes affected

PPBP (HGNC:9240): (pro-platelet basic protein) The protein encoded by this gene is a platelet-derived growth factor that belongs to the CXC chemokine family. This growth factor is a potent chemoattractant and activator of neutrophils. It has been shown to stimulate various cellular processes including DNA synthesis, mitosis, glycolysis, intracellular cAMP accumulation, prostaglandin E2 secretion, and synthesis of hyaluronic acid and sulfated glycosaminoglycan. It also stimulates the formation and secretion of plasminogen activator by synovial cells. The protein also is an antimicrobial protein with bactericidal and antifungal activity. [provided by RefSeq, Nov 2014]

ENSG00000288796 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0835067).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPBP	NM_002704.3	c.325G>A	p.Asp109Asn	missense_variant	Exon 3 of 3	ENST00000296028.4	NP_002695.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPBP	ENST00000296028.4	c.325G>A	p.Asp109Asn	missense_variant	Exon 3 of 3	1	NM_002704.3	ENSP00000296028.3
ENSG00000288796	ENST00000693342.1	c.325G>A	p.Asp109Asn	missense_variant	Exon 3 of 5			ENSP00000510492.1
ENSG00000288796	ENST00000689521.1	n.*158G>A		non_coding_transcript_exon_variant	Exon 3 of 6			ENSP00000509524.1
ENSG00000288796	ENST00000689521.1	n.*158G>A		3_prime_UTR_variant	Exon 3 of 6			ENSP00000509524.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461752 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.325G>A (p.D109N) alteration is located in exon 3 (coding exon 3) of the PPBP gene. This alteration results from a G to A substitution at nucleotide position 325, causing the aspartic acid (D) at amino acid position 109 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.44	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.023
Sift	Benign	0.17	T
Sift4G	Benign	0.13	T
Polyphen		0.0090	B
Vest4		0.21
MutPred		0.37		Gain of catalytic residue at D109 (P = 0.0088);
MVP		0.22
MPC		0.017
ClinPred		0.089	T
GERP RS		0.92
Varity_R		0.25
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1446904093; hg19: chr4-74853051;