chr12-9158460-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_002864.3(PZP):c.3254G>A(p.Cys1085Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
PZP
NM_002864.3 missense
NM_002864.3 missense
Scores
8
6
5
Clinical Significance
Conservation
PhyloP100: 4.56
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PZP | NM_002864.3 | c.3254G>A | p.Cys1085Tyr | missense_variant | 26/36 | ENST00000261336.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PZP | ENST00000261336.7 | c.3254G>A | p.Cys1085Tyr | missense_variant | 26/36 | 1 | NM_002864.3 | P1 | |
PZP | ENST00000535230.5 | c.*2723G>A | 3_prime_UTR_variant, NMD_transcript_variant | 23/33 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152160Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000995 AC: 25AN: 251366Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135874
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GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461886Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8AN XY: 727246
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74342
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 20, 2021 | The c.3254G>A (p.C1085Y) alteration is located in exon 26 (coding exon 26) of the PZP gene. This alteration results from a G to A substitution at nucleotide position 3254, causing the cysteine (C) at amino acid position 1085 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Uncertain
D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of disorder (P = 0.0569);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at