chr12-9168905-C-T

Variant names:

• chr12-9168905-C-T
• rs3213832
• NM_002864.3:c.2071G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002864.3(PZP):​c.2071G>A​(p.Val691Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0618 in 1,613,568 control chromosomes in the GnomAD database, including 3,751 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.082 (690 hom., cov: 33)
  • Exomes 𝑓: 0.060 (3061 hom.)
• Consequence: PZP NM_002864.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.561
• Publications: 17 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=0.0028637648).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PZP	NM_002864.3	c.2071G>A	p.Val691Met	missense_variant	Exon 17 of 36	ENST00000261336.7	NP_002855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PZP	ENST00000261336.7	c.2071G>A	p.Val691Met	missense_variant	Exon 17 of 36	1	NM_002864.3	ENSP00000261336.2

Frequencies

GnomAD3 genomes AF: 0.0817 AC: 12418 AN: 152082 Hom.: 683 Cov.: 33

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.0648

Gnomad AMR AF: 0.0435

Gnomad ASJ AF: 0.0733

Gnomad EAS AF: 0.0385

Gnomad SAS AF: 0.0998

Gnomad FIN AF: 0.0242

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0575

Gnomad OTH AF: 0.0657

GnomAD2 exomes AF: 0.0624 AC: 15685 AN: 251320 AF XY: 0.0639

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.0287

Gnomad ASJ exome AF: 0.0688

Gnomad EAS exome AF: 0.0399

Gnomad FIN exome AF: 0.0257

Gnomad NFE exome AF: 0.0585

Gnomad OTH exome AF: 0.0607

GnomAD4 exome AF: 0.0597 AC: 87223 AN: 1461368 Hom.: 3061 Cov.: 30 AF XY: 0.0611 AC XY: 44424 AN XY: 726974

African (AFR) AF: 0.156 AC: 5216 AN: 33454

American (AMR) AF: 0.0299 AC: 1336 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0677 AC: 1769 AN: 26122

East Asian (EAS) AF: 0.0398 AC: 1580 AN: 39680

South Asian (SAS) AF: 0.102 AC: 8788 AN: 86208

European-Finnish (FIN) AF: 0.0261 AC: 1396 AN: 53414

Middle Eastern (MID) AF: 0.0956 AC: 551 AN: 5766

European-Non Finnish (NFE) AF: 0.0562 AC: 62453 AN: 1111636

Other (OTH) AF: 0.0685 AC: 4134 AN: 60368

GnomAD4 genome AF: 0.0818 AC: 12447 AN: 152200 Hom.: 690 Cov.: 33 AF XY: 0.0795 AC XY: 5922 AN XY: 74446

African (AFR) AF: 0.156 AC: 6454 AN: 41500

American (AMR) AF: 0.0435 AC: 665 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0733 AC: 254 AN: 3464

East Asian (EAS) AF: 0.0386 AC: 200 AN: 5186

South Asian (SAS) AF: 0.101 AC: 488 AN: 4824

European-Finnish (FIN) AF: 0.0242 AC: 256 AN: 10600

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0575 AC: 3912 AN: 68014

Other (OTH) AF: 0.0651 AC: 137 AN: 2106

Alfa AF: 0.0659 Hom.: 1875

Bravo AF: 0.0849

TwinsUK AF: 0.0596 AC: 221

ALSPAC AF: 0.0560 AC: 216

ESP6500AA AF: 0.150 AC: 663

ESP6500EA AF: 0.0610 AC: 525

ExAC AF: 0.0670 AC: 8135

Asia WGS AF: 0.100 AC: 348 AN: 3478

EpiCase AF: 0.0632

EpiControl AF: 0.0658

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.58
DANN	Benign	0.31
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.55	N
PhyloP100		-0.56
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.0050
Sift	Benign	0.21	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.010
MPC		0.083
ClinPred		0.00061	T
GERP RS		-2.9
Varity_R		0.029
gMVP		0.41
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs3213832; hg19: chr12-9321501; COSMIC: COSV54360343; COSMIC: COSV54360343;