Variant 13-113163018-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_003891.3(PROZ):c.269C>G(p.Pro90Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,555,888 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P90A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00086 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0018 ( 8 hom. )

Consequence

PROZ
NM_003891.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.234

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.055225372).

BS2

High AC in GnomAd4 at 131 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROZ	NM_003891.3 linkuse as main transcript	c.269C>G	p.Pro90Arg	missense_variant	4/8	ENST00000375547.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROZ	ENST00000375547.7 linkuse as main transcript	c.269C>G	p.Pro90Arg	missense_variant	4/8	1	NM_003891.3	P2	P22891-1
PROZ	ENST00000342783.5 linkuse as main transcript	c.335C>G	p.Pro112Arg	missense_variant	5/9	1		A2	P22891-2

Frequencies

GnomAD3 genomes

AF:

0.000863

AC:

131

AN:

151814

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000387

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00149

Gnomad OTH

AF:

0.00240

GnomAD3 exomes

AF:

0.000825

AC:

135

AN:

163702

Hom.:

AF XY:

0.000785

AC XY:

AN XY:

86668

show subpopulations

Gnomad AFR exome

AF:

0.000424

Gnomad AMR exome

AF:

0.000696

Gnomad ASJ exome

AF:

0.000580

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000431

Gnomad FIN exome

AF:

0.000128

Gnomad NFE exome

AF:

0.00154

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.00176

AC:

2477

AN:

1403958

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

1170

AN XY:

693050

show subpopulations

Gnomad4 AFR exome

AF:

0.000345

Gnomad4 AMR exome

AF:

0.000790

Gnomad4 ASJ exome

AF:

0.000396

Gnomad4 EAS exome

AF:

0.0000277

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.000142

Gnomad4 NFE exome

AF:

0.00215

Gnomad4 OTH exome

AF:

0.00162

GnomAD4 genome

AF:

0.000862

AC:

131

AN:

151930

Hom.:

Cov.:

AF XY:

0.000768

AC XY:

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.000386

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00149

Gnomad4 OTH

AF:

0.00238

Alfa

AF:

0.000873

Hom.:

Bravo

AF:

0.000960

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000943

AC:

ExAC

AF:

0.000158

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.269C>G (p.P90R) alteration is located in exon 4 (coding exon 4) of the PROZ gene. This alteration results from a C to G substitution at nucleotide position 269, causing the proline (P) at amino acid position 90 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.22

CADD

Benign

8.4

DANN

Benign

0.092

DEOGEN2

Uncertain

0.45

.;T

Eigen

Benign

-0.87

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.57

T;T

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.055

T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.2

.;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.38

N;N

REVEL

Uncertain

0.36

Sift

Benign

0.79

T;T

Sift4G

Benign

0.75

T;T

Polyphen

0.68

P;B

Vest4

0.22

MVP

0.90

MPC

0.17

ClinPred

0.030

GERP RS

0.40

Varity_R

0.18

gMVP

0.67

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