13-113158713-A-G

Variant names:

• chr13-113158713-A-G
• rs777643858
• NM_003891.3:c.53A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003891.3(PROZ):​c.53A>G​(p.His18Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: PROZ NM_003891.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.119

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15498674).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROZ	NM_003891.3	c.53A>G	p.His18Arg	missense_variant	Exon 1 of 8	ENST00000375547.7	NP_003882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROZ	ENST00000375547.7	c.53A>G	p.His18Arg	missense_variant	Exon 1 of 8	1	NM_003891.3	ENSP00000364697.2
PROZ	ENST00000342783.5	c.53A>G	p.His18Arg	missense_variant	Exon 1 of 9	1		ENSP00000344458.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.53A>G (p.H18R) alteration is located in exon 1 (coding exon 1) of the PROZ gene. This alteration results from a A to G substitution at nucleotide position 53, causing the histidine (H) at amino acid position 18 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	0.066
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	2.2
DANN	Benign	0.48
DEOGEN2	Uncertain	0.51	.;D
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.46	T;T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Uncertain	0.031	D
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.5	N;D
REVEL	Benign	0.24
Sift	Benign	0.058	T;D
Sift4G	Pathogenic	0.0	D;T
Polyphen		0.0	B;P
Vest4		0.21
MutPred		0.59		Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);
MVP		0.96
MPC		0.17
ClinPred		0.072	T
GERP RS		-0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.54

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: rs777643858; hg19: chr13-113813027;