rs2277413

Variant names:

• chr12-9165188-A-G
• rs2277413
• NM_002864.3:c.2438T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-9165188-A-G
• chr12-9165188-A-T

Variant summary

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

The NM_002864.3(PZP):​c.2438T>C​(p.Val813Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 1,602,598 control chromosomes in the GnomAD database, including 80,844 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 0.32 (7912 hom., cov: 32)
  • Exomes 𝑓: 0.31 (72932 hom.)
• Consequence: PZP NM_002864.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.13
• 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]

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

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=6.5282475E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PZP	NM_002864.3	c.2438T>C	p.Val813Ala	missense_variant	Exon 19 of 36	ENST00000261336.7	NP_002855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PZP	ENST00000261336.7	c.2438T>C	p.Val813Ala	missense_variant	Exon 19 of 36	1	NM_002864.3	ENSP00000261336.2

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48228 AN: 151934 Hom.: 7917 Cov.: 32

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.360

Gnomad AMR AF: 0.266

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.544

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.320

GnomAD2 exomes AF: 0.323 AC: 80681 AN: 250108 AF XY: 0.333

Gnomad AFR exome AF: 0.332

Gnomad AMR exome AF: 0.191

Gnomad ASJ exome AF: 0.326

Gnomad EAS exome AF: 0.555

Gnomad FIN exome AF: 0.254

Gnomad NFE exome AF: 0.298

Gnomad OTH exome AF: 0.320

GnomAD4 exome AF: 0.307 AC: 445945 AN: 1450546 Hom.: 72932 Cov.: 44 AF XY: 0.313 AC XY: 225864 AN XY: 720878

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.332 AC: 11019 AN: 33140

American (AMR) AF: 0.197 AC: 8728 AN: 44364

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 8515 AN: 25880

East Asian (EAS) AF: 0.511 AC: 20226 AN: 39586

South Asian (SAS) AF: 0.464 AC: 39741 AN: 85572

European-Finnish (FIN) AF: 0.253 AC: 13476 AN: 53226

Middle Eastern (MID) AF: 0.430 AC: 2466 AN: 5736

European-Non Finnish (NFE) AF: 0.292 AC: 322274 AN: 1103060

Other (OTH) AF: 0.325 AC: 19500 AN: 59982

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.317 AC: 48238 AN: 152052 Hom.: 7912 Cov.: 32 AF XY: 0.320 AC XY: 23782 AN XY: 74308

African (AFR) AF: 0.336 AC: 13947 AN: 41480

American (AMR) AF: 0.265 AC: 4055 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 1121 AN: 3470

East Asian (EAS) AF: 0.544 AC: 2809 AN: 5162

South Asian (SAS) AF: 0.460 AC: 2210 AN: 4808

European-Finnish (FIN) AF: 0.257 AC: 2720 AN: 10572

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.298 AC: 20271 AN: 67972

Other (OTH) AF: 0.320 AC: 674 AN: 2108

Alfa AF: 0.309 Hom.: 5497

Bravo AF: 0.316

ESP6500AA AF: 0.332 AC: 1464

ESP6500EA AF: 0.295 AC: 2537

ExAC AF: 0.330 AC: 40022

Asia WGS AF: 0.463 AC: 1609 AN: 3478

EpiCase AF: 0.319

EpiControl AF: 0.315

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.4
DANN	Benign	0.25
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0000065	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-1.1
PrimateAI	Benign	0.29	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.025
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.016
MPC		0.10
ClinPred		0.00030	T
GERP RS		-0.93
Varity_R		0.030
gMVP		0.46
Mutation Taster		=99/1	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: rs2277413; hg19: chr12-9317784; COSMIC: COSV54357950; COSMIC: COSV54357950;