Genetic Variant PROZ:p.Pro90Leu (chr13-113163018-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_003891.3(PROZ):c.269C>T(p.Pro90Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000707 in 1,555,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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 0.000026 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

PROZ
NM_003891.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.234

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

protein Z deficiency
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

PROZ links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39310813).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003891.3. 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
	PROZ	NM_003891.3	MANE Select	c.269C>T	p.Pro90Leu	missense	Exon 4 of 8	NP_003882.1	P22891-1
	PROZ	NM_001256134.2		c.335C>T	p.Pro112Leu	missense	Exon 5 of 9	NP_001243063.1	P22891-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PROZ	ENST00000375547.7	TSL:1 MANE Select	c.269C>T	p.Pro90Leu	missense	Exon 4 of 8	ENSP00000364697.2	P22891-1
PROZ	ENST00000342783.5	TSL:1	c.335C>T	p.Pro112Leu	missense	Exon 5 of 9	ENSP00000344458.4	P22891-2
PROZ	ENST00000906454.1		c.416C>T	p.Pro139Leu	missense	Exon 6 of 10	ENSP00000576513.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151816

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000611

AC:

AN:

163702

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000106

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000499

AC:

AN:

1403962

Hom.:

Cov.:

AF XY:

0.00000577

AC XY:

AN XY:

693052

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31856

American (AMR)

AF:

0.00

AC:

AN:

36692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25234

East Asian (EAS)

AF:

0.0000277

AC:

AN:

36166

South Asian (SAS)

AF:

0.0000251

AC:

AN:

79564

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00000370

AC:

AN:

1081176

Other (OTH)

AF:

0.00

AC:

AN:

58168

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151816

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74128

show subpopulations

African (AFR)

AF:

0.0000726

AC:

AN:

41332

American (AMR)

AF:

0.00

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5124

South Asian (SAS)

AF:

0.00

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67924

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000176

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.59

DEOGEN2

Pathogenic

0.83

Eigen

Benign

-0.92

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.093

LIST_S2

Benign

0.77

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.39

MetaSVM

Pathogenic

0.87

MutationAssessor

Benign

1.2

PhyloP100

0.23

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.35

Sift

Benign

0.10

Sift4G

Benign

0.17

Polyphen

0.93

Vest4

0.33

MutPred

0.62

Loss of methylation at K86 (P = 0.0523)

MVP

0.85

MPC

0.45

ClinPred

0.50

GERP RS

0.40

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.20

gMVP

0.65

Mutation Taster

=91/9

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over