Genetic Variant PZP:c.1840-1518T>C (chr12-9171109-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002864.3(PZP):c.1840-1518T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.716 in 152,068 control chromosomes in the GnomAD database, including 39,297 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 0.72 ( 39297 hom., cov: 31)

Consequence

PZP
NM_002864.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.78

Publications

8 publications found

Variant links:

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 links:

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

LINC00987 links:

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]

KLRG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.02).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.846 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PZP	NM_002864.3 link	c.1840-1518T>C		intron_variant	Intron 15 of 35	ENST00000261336.7	NP_002855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PZP	ENST00000261336.7 link	c.1840-1518T>C		intron_variant	Intron 15 of 35	1	NM_002864.3	ENSP00000261336.2		P20742-1

Frequencies

GnomAD3 genomes

AF:

0.716

AC:

108863

AN:

151950

Hom.:

39288

Cov.:

show subpopulations

Gnomad AFR

AF:

0.723

Gnomad AMI

AF:

0.714

Gnomad AMR

AF:

0.634

Gnomad ASJ

AF:

0.769

Gnomad EAS

AF:

0.868

Gnomad SAS

AF:

0.855

Gnomad FIN

AF:

0.652

Gnomad MID

AF:

0.766

Gnomad NFE

AF:

0.717

Gnomad OTH

AF:

0.712

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.716

AC:

108906

AN:

152068

Hom.:

39297

Cov.:

AF XY:

0.714

AC XY:

53052

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.723

AC:

29952

AN:

41450

American (AMR)

AF:

0.633

AC:

9665

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.769

AC:

2668

AN:

3468

East Asian (EAS)

AF:

0.867

AC:

4467

AN:

5152

South Asian (SAS)

AF:

0.853

AC:

4118

AN:

4830

European-Finnish (FIN)

AF:

0.652

AC:

6901

AN:

10588

Middle Eastern (MID)

AF:

0.772

AC:

227

AN:

294

European-Non Finnish (NFE)

AF:

0.717

AC:

48749

AN:

67986

Other (OTH)

AF:

0.715

AC:

1509

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1624

3248

4873

6497

8121

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

842

1684

2526

3368

4210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.723

Hom.:

62146

Bravo

AF:

0.712

Asia WGS

AF:

0.838

AC:

2914

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.41

(source)

DANN

Benign

0.56

PhyloP100

-2.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over