rs10842971

Variant names:

• chr12-9150700-A-T
• rs10842971
• NM_002864.3:c.4328T>A

Variant summary

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

The NM_002864.3(PZP):​c.4328T>A​(p.Ile1443Asn) variant causes a missense change. The variant allele was found at a frequency of 0.291 in 1,609,768 control chromosomes in the GnomAD database, including 72,065 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 (5599 hom., cov: 32)
  • Exomes 𝑓: 0.29 (66466 hom.)
• Consequence: PZP NM_002864.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.96
• Publications: 34 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]

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

ENSG00000309149 (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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.004720241).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002864.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PZP	NM_002864.3	MANE Select	c.4328T>A	p.Ile1443Asn	missense	Exon 34 of 36	NP_002855.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PZP	ENST00000261336.7	TSL:1 MANE Select	c.4328T>A	p.Ile1443Asn	missense	Exon 34 of 36	ENSP00000261336.2
	PZP	ENST00000535230.5	TSL:1	n.*3797T>A		non_coding_transcript_exon	Exon 31 of 33	ENSP00000440811.1
	PZP	ENST00000535230.5	TSL:1	n.*3797T>A		3_prime_UTR	Exon 31 of 33	ENSP00000440811.1

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38516 AN: 151952 Hom.: 5594 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.0633

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.247

GnomAD2 exomes AF: 0.271 AC: 67841 AN: 250188 AF XY: 0.269

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.348

Gnomad ASJ exome AF: 0.216

Gnomad EAS exome AF: 0.0680

Gnomad FIN exome AF: 0.347

Gnomad NFE exome AF: 0.309

Gnomad OTH exome AF: 0.276

GnomAD4 exome AF: 0.295 AC: 429388 AN: 1457700 Hom.: 66466 Cov.: 32 AF XY: 0.292 AC XY: 211509 AN XY: 725390

African (AFR) AF: 0.125 AC: 4159 AN: 33380

American (AMR) AF: 0.347 AC: 15385 AN: 44338

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 5557 AN: 26098

East Asian (EAS) AF: 0.0590 AC: 2338 AN: 39636

South Asian (SAS) AF: 0.209 AC: 17985 AN: 85982

European-Finnish (FIN) AF: 0.348 AC: 18542 AN: 53356

Middle Eastern (MID) AF: 0.211 AC: 1216 AN: 5750

European-Non Finnish (NFE) AF: 0.314 AC: 348049 AN: 1108926

Other (OTH) AF: 0.268 AC: 16157 AN: 60234

GnomAD4 genome AF: 0.253 AC: 38541 AN: 152068 Hom.: 5599 Cov.: 32 AF XY: 0.255 AC XY: 18992 AN XY: 74342

African (AFR) AF: 0.129 AC: 5366 AN: 41530

American (AMR) AF: 0.328 AC: 5011 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 782 AN: 3470

East Asian (EAS) AF: 0.0634 AC: 329 AN: 5188

South Asian (SAS) AF: 0.207 AC: 996 AN: 4810

European-Finnish (FIN) AF: 0.356 AC: 3757 AN: 10544

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.316 AC: 21447 AN: 67956

Other (OTH) AF: 0.247 AC: 518 AN: 2100

Alfa AF: 0.292 Hom.: 5180

Bravo AF: 0.244

TwinsUK AF: 0.308 AC: 1141

ALSPAC AF: 0.314 AC: 1211

ESP6500AA AF: 0.142 AC: 625

ESP6500EA AF: 0.298 AC: 2559

ExAC AF: 0.268 AC: 32548

Asia WGS AF: 0.155 AC: 538 AN: 3478

EpiCase AF: 0.298

EpiControl AF: 0.286

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Benign	0.87
DEOGEN2	Benign	0.33	T
Eigen	Benign	0.035
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.0
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Benign	0.18
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.092	T
Polyphen		1.0	D
Vest4		0.12
MPC		0.40
ClinPred		0.070	T
GERP RS		4.2
Varity_R		0.77
gMVP		0.35
Mutation Taster		=97/3	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: rs10842971; hg19: chr12-9303296; COSMIC: COSV54356716;