12-9164177-T-C

Position:

• chr12-9164177-T-C

Variant summary

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

The NM_002864.3(PZP):​c.2570A>G​(p.Asn857Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 1,609,658 control chromosomes in the GnomAD database, including 145,211 homozygotes. 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.41 (12932 hom., cov: 32)
  • Exomes 𝑓: 0.42 (132279 hom.)
• Consequence: PZP NM_002864.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.60

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]

PZP (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040031075).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PZP	NM_002864.3	c.2570A>G	p.Asn857Ser	missense_variant	20/36	ENST00000261336.7	NP_002855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PZP	ENST00000261336.7	c.2570A>G	p.Asn857Ser	missense_variant	20/36	1	NM_002864.3	ENSP00000261336.2

Frequencies

GnomAD3 genomes AF: 0.411 AC: 62449 AN: 151958 Hom.: 12934 Cov.: 32

Gnomad AFR AF: 0.413

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.419

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.420

Gnomad OTH AF: 0.403

GnomAD3 exomes AF: 0.410 AC: 103121 AN: 251388 Hom.: 21295 AF XY: 0.409 AC XY: 55556 AN XY: 135872

Gnomad AFR exome AF: 0.414

Gnomad AMR exome AF: 0.376

Gnomad ASJ exome AF: 0.468

Gnomad EAS exome AF: 0.409

Gnomad SAS exome AF: 0.385

Gnomad FIN exome AF: 0.398

Gnomad NFE exome AF: 0.425

Gnomad OTH exome AF: 0.409

GnomAD4 exome AF: 0.424 AC: 618214 AN: 1457582 Hom.: 132279 Cov.: 37 AF XY: 0.423 AC XY: 306667 AN XY: 725360

Gnomad4 AFR exome AF: 0.413

Gnomad4 AMR exome AF: 0.375

Gnomad4 ASJ exome AF: 0.463

Gnomad4 EAS exome AF: 0.463

Gnomad4 SAS exome AF: 0.383

Gnomad4 FIN exome AF: 0.406

Gnomad4 NFE exome AF: 0.429

Gnomad4 OTH exome AF: 0.418

GnomAD4 genome AF: 0.411 AC: 62464 AN: 152076 Hom.: 12932 Cov.: 32 AF XY: 0.405 AC XY: 30139 AN XY: 74328

Gnomad4 AFR AF: 0.412

Gnomad4 AMR AF: 0.373

Gnomad4 ASJ AF: 0.456

Gnomad4 EAS AF: 0.419

Gnomad4 SAS AF: 0.402

Gnomad4 FIN AF: 0.390

Gnomad4 NFE AF: 0.420

Gnomad4 OTH AF: 0.406

Alfa AF: 0.420 Hom.: 33431

Bravo AF: 0.411

TwinsUK AF: 0.429 AC: 1591

ALSPAC AF: 0.430 AC: 1658

ESP6500AA AF: 0.418 AC: 1840

ESP6500EA AF: 0.430 AC: 3696

ExAC AF: 0.411 AC: 49867

Asia WGS AF: 0.394 AC: 1372 AN: 3478

EpiCase AF: 0.416

EpiControl AF: 0.427

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.096
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.087
Sift	Benign	0.044	D
Sift4G	Benign	0.088	T
Polyphen		0.95	P
Vest4		0.057
MPC		0.39
ClinPred		0.029	T
GERP RS		1.4
Varity_R		0.17
gMVP		0.095

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: rs3213831; hg19: chr12-9316773; COSMIC: COSV54361449; COSMIC: COSV54361449;