12-9153262-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_002864.3(PZP):c.3856G>A(p.Val1286Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000222 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00050 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

PZP
NM_002864.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.320

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:

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 made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.005659014).

BP6

Variant 12-9153262-C-T is Benign according to our data. Variant chr12-9153262-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3785778.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PZP	NM_002864.3 link	c.3856G>A	p.Val1286Ile	missense_variant	Exon 30 of 36	ENST00000261336.7	NP_002855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PZP	ENST00000261336.7 link	c.3856G>A	p.Val1286Ile	missense_variant	Exon 30 of 36	1	NM_002864.3	ENSP00000261336.2	P20742-1
PZP	ENST00000535230.5 link	n.*3325G>A		non_coding_transcript_exon_variant	Exon 27 of 33	1		ENSP00000440811.1	F5GXY0
PZP	ENST00000535230.5 link	n.*3325G>A		3_prime_UTR_variant	Exon 27 of 33	1		ENSP00000440811.1	F5GXY0

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000330

AC:

AN:

251434

Hom.:

AF XY:

0.000368

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00141

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000193

AC:

282

AN:

1461836

Hom.:

Cov.:

AF XY:

0.000221

AC XY:

161

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00164

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00141

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000692

Gnomad4 OTH exome

AF:

0.000281

GnomAD4 genome

AF:

0.000499

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00128

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000236

Hom.:

Bravo

AF:

0.000502

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000371

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Dec 31, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.25

DANN

Benign

0.29

DEOGEN2

Benign

0.047

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0057

LIST_S2

Benign

0.52

M_CAP

Benign

0.0022

MetaRNN

Benign

0.0057

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.59

PrimateAI

Benign

0.28

PROVEAN

Benign

0.40

REVEL

Benign

0.026

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0050

Vest4

0.095

MVP

0.048

MPC

0.068

ClinPred

0.0098

GERP RS

-4.2

Varity_R

0.023

gMVP

0.10

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over