13-113163009-G-A

Position:

• chr13-113163009-G-A

Variant summary

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

The NM_003891.3(PROZ):​c.260G>A​(p.Gly87Asp) variant causes a missense, splice region 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. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: PROZ NM_003891.3 missense, splice_region
• Scores: Splicing: ADA: 0.01584
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.222

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=0.2283116).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROZ	NM_003891.3	c.260G>A	p.Gly87Asp	missense_variant, splice_region_variant	4/8	ENST00000375547.7	NP_003882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROZ	ENST00000375547.7	c.260G>A	p.Gly87Asp	missense_variant, splice_region_variant	4/8	1	NM_003891.3	ENSP00000364697.2
PROZ	ENST00000342783.5	c.326G>A	p.Gly109Asp	missense_variant, splice_region_variant	5/9	1		ENSP00000344458.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.260G>A (p.G87D) alteration is located in exon 4 (coding exon 4) of the PROZ gene. This alteration results from a G to A substitution at nucleotide position 260, causing the glycine (G) at amino acid position 87 to be replaced by an aspartic acid (D). 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	0.16
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	14
DANN	Benign	0.60
DEOGEN2	Uncertain	0.63	.;D
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.47	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	0.15	.;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	1.7	N;N
REVEL	Uncertain	0.55
Sift	Benign	0.74	T;T
Sift4G	Benign	0.84	T;T
Polyphen		0.013	B;B
Vest4		0.45
MutPred		0.61		.;Loss of catalytic residue at G87 (P = 0.0407);
MVP		0.94
MPC		0.30
ClinPred		0.10	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.088
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.016
dbscSNV1_RF	Benign	0.32
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-113817323;