chr12-9194196-G-C

Variant names:

• chr12-9194196-G-C
• rs12230214
• NM_002864.3:c.1135C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002864.3(PZP):​c.1135C>G​(p.Leu379Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,613,096 control chromosomes in the GnomAD database, including 59,396 homozygotes. 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.

• Frequency:
  • Genomes: 𝑓 0.25 (4880 hom., cov: 31)
  • Exomes 𝑓: 0.27 (54516 hom.)
• Consequence: PZP NM_002864.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.419
• Publications: 23 publications found

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]

LINC00987 (HGNC:48911): (long intergenic non-protein coding RNA 987)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.365776E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PZP	NM_002864.3	c.1135C>G	p.Leu379Val	missense_variant	Exon 11 of 36	ENST00000261336.7	NP_002855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PZP	ENST00000261336.7	c.1135C>G	p.Leu379Val	missense_variant	Exon 11 of 36	1	NM_002864.3	ENSP00000261336.2

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37405 AN: 151960 Hom.: 4882 Cov.: 31

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.286

GnomAD2 exomes AF: 0.264 AC: 66434 AN: 251436 AF XY: 0.272

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.182

Gnomad ASJ exome AF: 0.230

Gnomad EAS exome AF: 0.430

Gnomad FIN exome AF: 0.249

Gnomad NFE exome AF: 0.269

Gnomad OTH exome AF: 0.287

GnomAD4 exome AF: 0.270 AC: 394401 AN: 1461018 Hom.: 54516 Cov.: 33 AF XY: 0.272 AC XY: 197482 AN XY: 726838

African (AFR) AF: 0.179 AC: 5982 AN: 33472

American (AMR) AF: 0.189 AC: 8435 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 6063 AN: 26120

East Asian (EAS) AF: 0.364 AC: 14443 AN: 39668

South Asian (SAS) AF: 0.301 AC: 25989 AN: 86228

European-Finnish (FIN) AF: 0.243 AC: 12984 AN: 53402

Middle Eastern (MID) AF: 0.335 AC: 1932 AN: 5768

European-Non Finnish (NFE) AF: 0.272 AC: 301830 AN: 1111288

Other (OTH) AF: 0.277 AC: 16743 AN: 60356

GnomAD4 genome AF: 0.246 AC: 37403 AN: 152078 Hom.: 4880 Cov.: 31 AF XY: 0.247 AC XY: 18348 AN XY: 74320

African (AFR) AF: 0.180 AC: 7459 AN: 41496

American (AMR) AF: 0.253 AC: 3861 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 801 AN: 3468

East Asian (EAS) AF: 0.400 AC: 2066 AN: 5170

South Asian (SAS) AF: 0.305 AC: 1466 AN: 4814

European-Finnish (FIN) AF: 0.240 AC: 2537 AN: 10556

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.270 AC: 18380 AN: 67986

Other (OTH) AF: 0.287 AC: 603 AN: 2104

Alfa AF: 0.266 Hom.: 4193

Bravo AF: 0.244

TwinsUK AF: 0.259 AC: 961

ALSPAC AF: 0.275 AC: 1059

ESP6500AA AF: 0.181 AC: 799

ESP6500EA AF: 0.279 AC: 2400

ExAC AF: 0.265 AC: 32112

Asia WGS AF: 0.313 AC: 1089 AN: 3478

EpiCase AF: 0.285

EpiControl AF: 0.281

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.24
DANN	Benign	0.12
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.0052	T
MetaRNN	Benign	0.00064	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.42
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.37	N
REVEL	Benign	0.020
Sift	Benign	0.73	T
Sift4G	Benign	0.73	T
Polyphen		0.0	B
Vest4		0.0050
MPC		0.083
ClinPred		0.00018	T
GERP RS		0.37
Varity_R		0.041
gMVP		0.25
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12230214; hg19: chr12-9346792; COSMIC: COSV54360192;