rs12822596

Variant names:

• chr12-9157399-G-A
• rs12822596
• NM_002864.3:c.3370-44C>T

Variant summary

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

The NM_002864.3(PZP):​c.3370-44C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 1,566,490 control chromosomes in the GnomAD database, including 70,369 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.

• Frequency:
  • Genomes: 𝑓 0.25 (5626 hom., cov: 32)
  • Exomes 𝑓: 0.30 (64743 hom.)
• Consequence: PZP NM_002864.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.18
• Publications: 8 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 (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PZP	NM_002864.3	c.3370-44C>T		intron_variant	Intron 27 of 35	ENST00000261336.7	NP_002855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PZP	ENST00000261336.7	c.3370-44C>T		intron_variant	Intron 27 of 35	1	NM_002864.3	ENSP00000261336.2

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38710 AN: 152002 Hom.: 5621 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.0633

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.249

GnomAD2 exomes AF: 0.273 AC: 62820 AN: 230300 AF XY: 0.270

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.353

Gnomad ASJ exome AF: 0.222

Gnomad EAS exome AF: 0.0692

Gnomad FIN exome AF: 0.353

Gnomad NFE exome AF: 0.311

Gnomad OTH exome AF: 0.284

GnomAD4 exome AF: 0.296 AC: 418624 AN: 1414370 Hom.: 64743 Cov.: 27 AF XY: 0.293 AC XY: 205169 AN XY: 700908

African (AFR) AF: 0.130 AC: 4181 AN: 32216

American (AMR) AF: 0.350 AC: 14729 AN: 42098

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 5341 AN: 24884

East Asian (EAS) AF: 0.0593 AC: 2323 AN: 39148

South Asian (SAS) AF: 0.210 AC: 17505 AN: 83382

European-Finnish (FIN) AF: 0.347 AC: 16443 AN: 47334

Middle Eastern (MID) AF: 0.225 AC: 1026 AN: 4552

European-Non Finnish (NFE) AF: 0.315 AC: 341281 AN: 1082308

Other (OTH) AF: 0.270 AC: 15795 AN: 58448

GnomAD4 genome AF: 0.255 AC: 38740 AN: 152120 Hom.: 5626 Cov.: 32 AF XY: 0.256 AC XY: 19064 AN XY: 74368

African (AFR) AF: 0.133 AC: 5531 AN: 41502

American (AMR) AF: 0.328 AC: 5011 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 782 AN: 3470

East Asian (EAS) AF: 0.0634 AC: 329 AN: 5186

South Asian (SAS) AF: 0.207 AC: 998 AN: 4822

European-Finnish (FIN) AF: 0.356 AC: 3760 AN: 10550

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.316 AC: 21496 AN: 67982

Other (OTH) AF: 0.249 AC: 526 AN: 2112

Alfa AF: 0.291 Hom.: 3581

Bravo AF: 0.245

Asia WGS AF: 0.154 AC: 535 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.2
DANN	Benign	0.55
PhyloP100		2.2
Mutation Taster		=100/0	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: rs12822596; hg19: chr12-9309995; COSMIC: COSV54373395; COSMIC: COSV54373395;