chr12-9162647-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_002864.3(PZP):c.2738C>T(p.Ala913Val) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
PZP
NM_002864.3 missense, splice_region
NM_002864.3 missense, splice_region
Scores
1
4
14
Splicing: ADA: 0.6202
2
Clinical Significance
Conservation
PhyloP100: 6.62
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 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.12270966).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PZP | NM_002864.3 | c.2738C>T | p.Ala913Val | missense_variant, splice_region_variant | 22/36 | ENST00000261336.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PZP | ENST00000261336.7 | c.2738C>T | p.Ala913Val | missense_variant, splice_region_variant | 22/36 | 1 | NM_002864.3 | P1 | |
PZP | ENST00000535230.5 | c.*2207C>T | splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant | 19/33 | 1 | ||||
PZP | ENST00000546197.5 | n.965-1531C>T | intron_variant, non_coding_transcript_variant | 1 | |||||
PZP | ENST00000539983.5 | n.1148C>T | splice_region_variant, non_coding_transcript_exon_variant | 6/9 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 249012Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134588
GnomAD3 exomes
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1
AN:
249012
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GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1437306Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 716352
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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1437306
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30
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716352
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GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ExAC
?
AF:
AC:
1
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 | Dec 27, 2023 | The c.2738C>T (p.A913V) alteration is located in exon 22 (coding exon 22) of the PZP gene. This alteration results from a C to T substitution at nucleotide position 2738, causing the alanine (A) at amino acid position 913 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
B
Vest4
MutPred
Gain of catalytic residue at A913 (P = 0.0782);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at