12-9153262-C-T

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

19

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]
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]

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
PZPNM_002864.3 linkc.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 Appris UniProt
PZPENST00000261336.7 linkc.3856G>A p.Val1286Ile missense_variant Exon 30 of 36 1 NM_002864.3 ENSP00000261336.2 P20742-1
PZPENST00000535230.5 linkn.*3325G>A non_coding_transcript_exon_variant Exon 27 of 33 1 ENSP00000440811.1 F5GXY0
PZPENST00000535230.5 linkn.*3325G>A 3_prime_UTR_variant Exon 27 of 33 1 ENSP00000440811.1 F5GXY0

Frequencies

GnomAD3 genomes
AF:
0.000493
AC:
75
AN:
152162
Hom.:
0
Cov.:
32
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:
83
AN:
251434
Hom.:
0
AF XY:
0.000368
AC XY:
50
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.:
0
Cov.:
32
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:
76
AN:
152280
Hom.:
0
Cov.:
32
AF XY:
0.000510
AC XY:
38
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.:
0
Bravo
AF:
0.000502
ESP6500AA
AF:
0.00113
AC:
5
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000371
AC:
45
Asia WGS
AF:
0.00144
AC:
5
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
T
BayesDel_noAF
Benign
-0.73
CADD
Benign
0.25
DANN
Benign
0.29
DEOGEN2
Benign
0.047
T
Eigen
Benign
-1.9
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.0057
N
LIST_S2
Benign
0.52
T
M_CAP
Benign
0.0022
T
MetaRNN
Benign
0.0057
T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
-0.59
N
PrimateAI
Benign
0.28
T
PROVEAN
Benign
0.40
N
REVEL
Benign
0.026
Sift
Benign
1.0
T
Sift4G
Benign
1.0
T
Polyphen
0.0050
B
Vest4
0.095
MVP
0.048
MPC
0.068
ClinPred
0.0098
T
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.

Other links and lift over

dbSNP: rs151314973; hg19: chr12-9305858; COSMIC: COSV54364248; COSMIC: COSV54364248; API