12-9150844-A-G

Variant names:

• chr12-9150844-A-G
• rs3741851
• NM_002864.3:c.4282-98T>C

Variant summary

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

The NM_002864.3(PZP):​c.4282-98T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 773,852 control chromosomes in the GnomAD database, including 16,373 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 0.18 (2895 hom., cov: 32)
  • Exomes 𝑓: 0.19 (13478 hom.)
• Consequence: PZP NM_002864.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12
• Publications: 5 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)

ENSG00000309149 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.458 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PZP	NM_002864.3	MANE Select	c.4282-98T>C		intron	N/A	NP_002855.2	P20742-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PZP	ENST00000261336.7	TSL:1 MANE Select	c.4282-98T>C		intron	N/A	ENSP00000261336.2	P20742-1
	PZP	ENST00000535230.5	TSL:1	n.*3751-98T>C		intron	N/A	ENSP00000440811.1	F5GXY0
	PZP	ENST00000882540.1		c.4312-98T>C		intron	N/A	ENSP00000552599.1

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27717 AN: 152054 Hom.: 2893 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.218

GnomAD4 exome AF: 0.193 AC: 120242 AN: 621680 Hom.: 13478 AF XY: 0.198 AC XY: 66431 AN XY: 334692

African (AFR) AF: 0.146 AC: 2280 AN: 15632

American (AMR) AF: 0.249 AC: 6688 AN: 26912

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 3670 AN: 19130

East Asian (EAS) AF: 0.404 AC: 13109 AN: 32414

South Asian (SAS) AF: 0.292 AC: 17683 AN: 60490

European-Finnish (FIN) AF: 0.139 AC: 5862 AN: 42322

Middle Eastern (MID) AF: 0.286 AC: 1163 AN: 4072

European-Non Finnish (NFE) AF: 0.163 AC: 63270 AN: 388766

Other (OTH) AF: 0.204 AC: 6517 AN: 31942

GnomAD4 genome AF: 0.182 AC: 27718 AN: 152172 Hom.: 2895 Cov.: 32 AF XY: 0.188 AC XY: 13955 AN XY: 74388

African (AFR) AF: 0.148 AC: 6162 AN: 41534

American (AMR) AF: 0.242 AC: 3708 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 590 AN: 3470

East Asian (EAS) AF: 0.474 AC: 2444 AN: 5156

South Asian (SAS) AF: 0.296 AC: 1426 AN: 4824

European-Finnish (FIN) AF: 0.148 AC: 1569 AN: 10584

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.163 AC: 11107 AN: 67994

Other (OTH) AF: 0.217 AC: 457 AN: 2108

Alfa AF: 0.176 Hom.: 11147

Bravo AF: 0.189

Asia WGS AF: 0.344 AC: 1193 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.49
DANN	Benign	0.51
PhyloP100		-1.1
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: rs3741851; hg19: chr12-9303440; COSMIC: COSV54356588;