13-113171786-G-A

Position:

chr13-113171786-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). 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

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.210

Variant links:

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]

PROZ links:

PCID2 (HGNC:):

PCID2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 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 no_assertion_criteria_provided, 0 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. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3539 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROZ	NM_003891.3 linkuse as main transcript	c.884G>A	p.Arg295His	missense_variant	8/8	ENST00000375547.7	NP_003882.1	P22891-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROZ	ENST00000375547.7 linkuse as main transcript	c.884G>A	p.Arg295His	missense_variant	8/8	1	NM_003891.3	ENSP00000364697.2		P22891-1
PROZ	ENST00000342783.5 linkuse as main transcript	c.950G>A	p.Arg317His	missense_variant	9/9	1		ENSP00000344458.4		P22891-2

Frequencies

GnomAD3 genomes

AF:

0.0233

AC:

3539

AN:

152168

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0252

AC XY:

3421

AN XY:

135602

show subpopulations

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.:

AF XY:

0.0300

AC XY:

21789

AN XY:

726356

show subpopulations

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.:

Cov.:

AF XY:

0.0220

AC XY:

1637

AN XY:

74452

show subpopulations

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:

ESP6500EA

AF:

0.0372

AC:

320

ExAC

AF:

0.0254

AC:

3079

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0371

EpiControl

AF:

0.0409

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

PROZ-related disorder

Benign:1

Likely benign, no assertion criteria provided

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

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

.;T

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.52

T;T

MetaRNN

Benign

0.0024

T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.8

.;L

PrimateAI

Benign

0.25

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over