chr12-9168905-C-A

Position:

• chr12-9168905-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002864.3(PZP):​c.2071G>T​(p.Val691Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V691M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PZP NM_002864.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.561

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 (HGNC:):

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057468385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PZP	NM_002864.3	c.2071G>T	p.Val691Leu	missense_variant	17/36	ENST00000261336.7	NP_002855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PZP	ENST00000261336.7	c.2071G>T	p.Val691Leu	missense_variant	17/36	1	NM_002864.3	ENSP00000261336.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.025
DANN	Benign	0.093
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.0070
Sift	Benign	0.99	T
Sift4G	Benign	0.69	T
Polyphen		0.0	B
Vest4		0.041
MutPred		0.34		Loss of sheet (P = 0.1907);
MVP		0.067
MPC		0.081
ClinPred		0.031	T
GERP RS		-2.9
Varity_R		0.032
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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

Other links and lift over

dbSNP: rs3213832; hg19: chr12-9321501;