chr13-113160128-T-A

Variant names:

• chr13-113160128-T-A
• rs146864768
• NM_003891.3:c.185T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003891.3(PROZ):​c.185T>A​(p.Ile62Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000717 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (0 hom.)
• Consequence: PROZ NM_003891.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.37
• Publications: 2 publications found

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)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10392782).

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.185T>A	p.Ile62Asn	missense	Exon 2 of 8	NP_003882.1	P22891-1
	PROZ	NM_001256134.2		c.251T>A	p.Ile84Asn	missense	Exon 3 of 9	NP_001243063.1	P22891-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROZ	ENST00000375547.7	TSL:1 MANE Select	c.185T>A	p.Ile62Asn	missense	Exon 2 of 8	ENSP00000364697.2	P22891-1
	PROZ	ENST00000342783.5	TSL:1	c.251T>A	p.Ile84Asn	missense	Exon 3 of 9	ENSP00000344458.4	P22891-2
	PROZ	ENST00000906454.1		c.332T>A	p.Ile111Asn	missense	Exon 4 of 10	ENSP00000576513.1

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000481 AC: 121 AN: 251488 AF XY: 0.000449

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000949

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000734 AC: 1073 AN: 1461812 Hom.: 0 Cov.: 32 AF XY: 0.000716 AC XY: 521 AN XY: 727200

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000300 AC: 16 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000921 AC: 1024 AN: 1112002

Other (OTH) AF: 0.000364 AC: 22 AN: 60396

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74460

African (AFR) AF: 0.0000963 AC: 4 AN: 41544

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000803 Hom.: 0

Bravo AF: 0.000427

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000593 AC: 72

EpiCase AF: 0.000436

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.10	T
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.4
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.44
Sift	Benign	0.17	T
Sift4G	Benign	0.097	T
Polyphen		0.26	B
Vest4		0.48
MVP		0.89
MPC		0.77
ClinPred		0.085	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.30
gMVP		0.71
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs146864768; hg19: chr13-113814442;