rs3024772

chr13-113171786-G-Achr13-113171786-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003891.3(PROZ):c.884G>A(p.Arg295His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0299 in 1,612,768 control chromosomes in the GnomAD database, including 877 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.023 (63 hom., cov: 32)
  • Exomes 𝑓: 0.031 (814 hom.)
• Consequence: PROZ NM_003891.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.210

Genes affected

PROZ (HGNC:9460): (protein Z, vitamin K dependent plasma glycoprotein) This gene encodes a liver vitamin K-dependent glycoprotein that is synthesized in the liver and secreted into the plasma. The encoded protein plays a role in regulating blood coagulation by complexing with protein Z-dependent protease inhibitor to directly inhibit activated factor X at the phospholipid surface. Deficiencies in this protein are associated with an increased risk of ischemic arterial diseases and fetal loss. Mutations in this gene are the cause of protein Z deficiency. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2012]

PCID2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023902655).
• BP6: Variant 13-113171786-G-A is Benign according to our data. Variant chr13-113171786-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3056128.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0232 (3539/152286) while in subpopulation NFE AF= 0.0367 (2497/68004). AF 95% confidence interval is 0.0355. There are 63 homozygotes in gnomad4. There are 1637 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 3539 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROZ	NM_003891.3	c.884G>A	p.Arg295His	missense_variant	8/8	ENST00000375547.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROZ	ENST00000375547.7	c.884G>A	p.Arg295His	missense_variant	8/8	1	NM_003891.3	P2
PROZ	ENST00000342783.5	c.950G>A	p.Arg317His	missense_variant	9/9	1		A2

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3539 AN: 152168 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.00591

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.0374

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.0171

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0367

Gnomad OTH AF: 0.0273

GnomAD3 exomes AF: 0.0245 AC: 6143 AN: 250738 Hom.: 96 AF XY: 0.0252 AC XY: 3421 AN XY: 135602

Gnomad AFR exome AF: 0.00617

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.0409

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00784

Gnomad FIN exome AF: 0.0202

Gnomad NFE exome AF: 0.0379

Gnomad OTH exome AF: 0.0254

GnomAD4 exome AF: 0.0305 AC: 44606 AN: 1460482 Hom.: 814 Cov.: 31 AF XY: 0.0300 AC XY: 21789 AN XY: 726356

Gnomad4 AFR exome AF: 0.00514

Gnomad4 AMR exome AF: 0.0158

Gnomad4 ASJ exome AF: 0.0366

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00821

Gnomad4 FIN exome AF: 0.0199

Gnomad4 NFE exome AF: 0.0353

Gnomad4 OTH exome AF: 0.0269

GnomAD4 genome AF: 0.0232 AC: 3539 AN: 152286 Hom.: 63 Cov.: 32 AF XY: 0.0220 AC XY: 1637 AN XY: 74452

Gnomad4 AFR AF: 0.00587

Gnomad4 AMR AF: 0.0204

Gnomad4 ASJ AF: 0.0374

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.0171

Gnomad4 NFE AF: 0.0367

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0343 Hom.: 218

Bravo AF: 0.0232

TwinsUK AF: 0.0326 AC: 121

ALSPAC AF: 0.0371 AC: 143

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0372 AC: 320

ExAC AF: 0.0254 AC: 3079

Asia WGS AF: 0.00520 AC: 19 AN: 3478

EpiCase AF: 0.0371

EpiControl AF: 0.0409

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PROZ-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	14
Dann	Uncertain	1.0
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.52	T;T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-0.51	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.27
Sift	Benign	0.087	T;T
Sift4G	Benign	0.15	T;T
Polyphen		1.0	D;D
Vest4		0.024
MPC		0.17
ClinPred		0.019	T
GERP RS		0.82
Varity_R		0.066
gMVP		0.44

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: rs3024772; hg19: chr13-113826100; COSMIC: COSV61439929; COSMIC: COSV61439929;