12-9157290-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_002864.3(PZP):c.3435C>T(p.Thr1145=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00416 in 1,614,060 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (24 hom.)
• Consequence: PZP NM_002864.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0730

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:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-9157290-G-A is Benign according to our data. Variant chr12-9157290-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2642692.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.073 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PZP	NM_002864.3	c.3435C>T	p.Thr1145=	synonymous_variant	28/36	ENST00000261336.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PZP	ENST00000261336.7	c.3435C>T	p.Thr1145=	synonymous_variant	28/36	1	NM_002864.3	P1
PZP	ENST00000535230.5	c.*2904C>T		3_prime_UTR_variant, NMD_transcript_variant	25/33	1

Frequencies

GnomAD3 genomes AF: 0.00274 AC: 417 AN: 152176 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00439

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00257 AC: 645 AN: 250744 Hom.: 2 AF XY: 0.00268 AC XY: 363 AN XY: 135508

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.000509

Gnomad NFE exome AF: 0.00409

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00431 AC: 6306 AN: 1461766 Hom.: 24 Cov.: 31 AF XY: 0.00421 AC XY: 3058 AN XY: 727194

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00280

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00144

Gnomad4 FIN exome AF: 0.000524

Gnomad4 NFE exome AF: 0.00516

Gnomad4 OTH exome AF: 0.00422

GnomAD4 genome AF: 0.00273 AC: 416 AN: 152294 Hom.: 2 Cov.: 32 AF XY: 0.00228 AC XY: 170 AN XY: 74466

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00503

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00440

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00349 Hom.: 1

Bravo AF: 0.00329

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00436

EpiControl AF: 0.00326

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2022

PZP: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	1.4
Dann	Benign	0.49

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: rs35095552; hg19: chr12-9309886;