rs12822596

Positions:

• chr12-9157399-G-A

Variant summary

Our verdict is Benign. Variant got -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

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:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
PZP	NM_002864.3	c.3370-44C>T		intron_variant		ENST00000261336.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PZP	ENST00000261336.7	c.3370-44C>T		intron_variant		1	NM_002864.3	P1
PZP	ENST00000535230.5	c.*2839-44C>T		intron_variant, NMD_transcript_variant		1

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

GnomAD3 exomes AF: 0.273 AC: 62820 AN: 230300 Hom.: 9500 AF XY: 0.270 AC XY: 33896 AN XY: 125324

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 SAS exome AF: 0.206

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

Gnomad4 AFR exome AF: 0.130

Gnomad4 AMR exome AF: 0.350

Gnomad4 ASJ exome AF: 0.215

Gnomad4 EAS exome AF: 0.0593

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.347

Gnomad4 NFE exome AF: 0.315

Gnomad4 OTH exome AF: 0.270

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

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.328

Gnomad4 ASJ AF: 0.225

Gnomad4 EAS AF: 0.0634

Gnomad4 SAS AF: 0.207

Gnomad4 FIN AF: 0.356

Gnomad4 NFE AF: 0.316

Gnomad4 OTH AF: 0.249

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

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: rs12822596; hg19: chr12-9309995; COSMIC: COSV54373395; COSMIC: COSV54373395;