rs12230214

Positions:

• chr12-9194196-G-C

Variant summary

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

The NM_002864.3(PZP):​c.1135C>G​(p.Leu379Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,613,096 control chromosomes in the GnomAD database, including 59,396 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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.

• Frequency:
  • Genomes: 𝑓 0.25 (4880 hom., cov: 31)
  • Exomes 𝑓: 0.27 (54516 hom.)
• Consequence: PZP NM_002864.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.419

Genes affected

PZP (HGNC:9750): (PZP alpha-2-macroglobulin like) The protein encoded by this gene is highly expressed in late-pregnancy serum and is similar in structure to alpha-2-macroglobulin. The encoded protein, which acts as a homotetramer, inhibits the activity of all four classes of proteinases. This protein contains cleavage sites for several proteinases. Upon binding of a proteinase, the conformation of this protein changes to trap the proteinase, limiting its activity. This protein appears to be elevated in the sera of presymptomatic Alzheimer's disease patients. [provided by RefSeq, Dec 2016]

KLRG1 (HGNC:6380): (killer cell lectin like receptor G1) Natural killer (NK) cells are lymphocytes that can mediate lysis of certain tumor cells and virus-infected cells without previous activation. They can also regulate specific humoral and cell-mediated immunity. The protein encoded by this gene belongs to the killer cell lectin-like receptor (KLR) family, which is a group of transmembrane proteins preferentially expressed in NK cells. Studies in mice suggested that the expression of this gene may be regulated by MHC class I molecules. [provided by RefSeq, Jun 2016]

PZP (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.365776E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PZP	NM_002864.3	c.1135C>G	p.Leu379Val	missense_variant	11/36	ENST00000261336.7	NP_002855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PZP	ENST00000261336.7	c.1135C>G	p.Leu379Val	missense_variant	11/36	1	NM_002864.3	ENSP00000261336.2
PZP	ENST00000535230.5	n.*853C>G		non_coding_transcript_exon_variant	10/33	1		ENSP00000440811.1
PZP	ENST00000535230.5	n.*853C>G		3_prime_UTR_variant	10/33	1		ENSP00000440811.1

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37405 AN: 151960 Hom.: 4882 Cov.: 31

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.286

GnomAD3 exomes AF: 0.264 AC: 66434 AN: 251436 Hom.: 9372 AF XY: 0.272 AC XY: 36954 AN XY: 135882

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.182

Gnomad ASJ exome AF: 0.230

Gnomad EAS exome AF: 0.430

Gnomad SAS exome AF: 0.302

Gnomad FIN exome AF: 0.249

Gnomad NFE exome AF: 0.269

Gnomad OTH exome AF: 0.287

GnomAD4 exome AF: 0.270 AC: 394401 AN: 1461018 Hom.: 54516 Cov.: 33 AF XY: 0.272 AC XY: 197482 AN XY: 726838

Gnomad4 AFR exome AF: 0.179

Gnomad4 AMR exome AF: 0.189

Gnomad4 ASJ exome AF: 0.232

Gnomad4 EAS exome AF: 0.364

Gnomad4 SAS exome AF: 0.301

Gnomad4 FIN exome AF: 0.243

Gnomad4 NFE exome AF: 0.272

Gnomad4 OTH exome AF: 0.277

GnomAD4 genome AF: 0.246 AC: 37403 AN: 152078 Hom.: 4880 Cov.: 31 AF XY: 0.247 AC XY: 18348 AN XY: 74320

Gnomad4 AFR AF: 0.180

Gnomad4 AMR AF: 0.253

Gnomad4 ASJ AF: 0.231

Gnomad4 EAS AF: 0.400

Gnomad4 SAS AF: 0.305

Gnomad4 FIN AF: 0.240

Gnomad4 NFE AF: 0.270

Gnomad4 OTH AF: 0.287

Alfa AF: 0.266 Hom.: 4193

Bravo AF: 0.244

TwinsUK AF: 0.259 AC: 961

ALSPAC AF: 0.275 AC: 1059

ESP6500AA AF: 0.181 AC: 799

ESP6500EA AF: 0.279 AC: 2400

ExAC AF: 0.265 AC: 32112

Asia WGS AF: 0.313 AC: 1089 AN: 3478

EpiCase AF: 0.285

EpiControl AF: 0.281

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.24
DANN	Benign	0.12
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.0052	T
MetaRNN	Benign	0.00064	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.0	L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.37	N
REVEL	Benign	0.020
Sift	Benign	0.73	T
Sift4G	Benign	0.73	T
Polyphen		0.0	B
Vest4		0.0050
MPC		0.083
ClinPred		0.00018	T
GERP RS		0.37
Varity_R		0.041
gMVP		0.25

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: rs12230214; hg19: chr12-9346792; COSMIC: COSV54360192;