12-9171109-A-G

Variant names:

• chr12-9171109-A-G
• rs2114847
• NM_002864.3:c.1840-1518T>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002864.3(PZP):​c.1840-1518T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.716 in 152,068 control chromosomes in the GnomAD database, including 39,297 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.72 (39297 hom., cov: 31)
• Consequence: PZP NM_002864.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.78

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.846 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PZP	NM_002864.3	c.1840-1518T>C		intron_variant	Intron 15 of 35	ENST00000261336.7	NP_002855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PZP	ENST00000261336.7	c.1840-1518T>C		intron_variant	Intron 15 of 35	1	NM_002864.3	ENSP00000261336.2
PZP	ENST00000535230.5	n.*1558-1518T>C		intron_variant	Intron 14 of 32	1		ENSP00000440811.1

Frequencies

GnomAD3 genomes AF: 0.716 AC: 108863 AN: 151950 Hom.: 39288 Cov.: 31

Gnomad AFR AF: 0.723

Gnomad AMI AF: 0.714

Gnomad AMR AF: 0.634

Gnomad ASJ AF: 0.769

Gnomad EAS AF: 0.868

Gnomad SAS AF: 0.855

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.717

Gnomad OTH AF: 0.712

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.716 AC: 108906 AN: 152068 Hom.: 39297 Cov.: 31 AF XY: 0.714 AC XY: 53052 AN XY: 74330

Gnomad4 AFR AF: 0.723

Gnomad4 AMR AF: 0.633

Gnomad4 ASJ AF: 0.769

Gnomad4 EAS AF: 0.867

Gnomad4 SAS AF: 0.853

Gnomad4 FIN AF: 0.652

Gnomad4 NFE AF: 0.717

Gnomad4 OTH AF: 0.715

Alfa AF: 0.725 Hom.: 49113

Bravo AF: 0.712

Asia WGS AF: 0.838 AC: 2914 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.41
DANN	Benign	0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs2114847; hg19: chr12-9323705;