12-9164177-T-C

Variant names:

• chr12-9164177-T-C
• rs3213831
• NM_002864.3:c.2570A>G

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 35 publications found

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]

LINC00987 (HGNC:48911): (long intergenic non-protein coding RNA 987)

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PZP	NM_002864.3	c.2570A>G	p.Asn857Ser	missense_variant	Exon 20 of 36	ENST00000261336.7	NP_002855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PZP	ENST00000261336.7	c.2570A>G	p.Asn857Ser	missense_variant	Exon 20 of 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

GnomAD2 exomes AF: 0.410 AC: 103121 AN: 251388 AF XY: 0.409

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 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

African (AFR) AF: 0.413 AC: 13775 AN: 33380

American (AMR) AF: 0.375 AC: 16763 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 12085 AN: 26092

East Asian (EAS) AF: 0.463 AC: 18367 AN: 39668

South Asian (SAS) AF: 0.383 AC: 32963 AN: 86108

European-Finnish (FIN) AF: 0.406 AC: 21657 AN: 53320

Middle Eastern (MID) AF: 0.337 AC: 1942 AN: 5760

European-Non Finnish (NFE) AF: 0.429 AC: 475485 AN: 1108296

Other (OTH) AF: 0.418 AC: 25177 AN: 60260

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

African (AFR) AF: 0.412 AC: 17108 AN: 41482

American (AMR) AF: 0.373 AC: 5697 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 1583 AN: 3468

East Asian (EAS) AF: 0.419 AC: 2163 AN: 5164

South Asian (SAS) AF: 0.402 AC: 1938 AN: 4818

European-Finnish (FIN) AF: 0.390 AC: 4124 AN: 10564

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.420 AC: 28539 AN: 67978

Other (OTH) AF: 0.406 AC: 859 AN: 2114

Alfa AF: 0.420 Hom.: 60637

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
PhyloP100		2.6
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
Mutation Taster		=99/1	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

Other links and lift over

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