13-113164643-C-A

Position:

• chr13-113164643-C-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.504C>A​(p.His168Gln) 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. 17/23 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: 33)
• Consequence: PROZ NM_003891.3 missense, splice_region
• Scores: Splicing: ADA: 0.00004846
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.321

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=0.078445435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROZ	NM_003891.3	c.504C>A	p.His168Gln	missense_variant, splice_region_variant	5/8	ENST00000375547.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROZ	ENST00000375547.7	c.504C>A	p.His168Gln	missense_variant, splice_region_variant	5/8	1	NM_003891.3	P2
PROZ	ENST00000342783.5	c.570C>A	p.His190Gln	missense_variant, splice_region_variant	6/9	1		A2
PROZ	ENST00000493630.1	n.125C>A		splice_region_variant, non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 33

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

May 24, 2023

The c.504C>A (p.H168Q) alteration is located in exon 5 (coding exon 5) of the PROZ gene. This alteration results from a C to A substitution at nucleotide position 504, causing the histidine (H) at amino acid position 168 to be replaced by a glutamine (Q). 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	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.15
DANN	Benign	0.68
DEOGEN2	Benign	0.27	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.46	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.078	T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	-0.46	.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.55	N;N
REVEL	Benign	0.21
Sift	Benign	0.24	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.30	B;B
Vest4		0.16
MutPred		0.40		.;Gain of disorder (P = 0.0498);
MVP		0.94
MPC		0.22
ClinPred		0.30	T
GERP RS		-3.3
Varity_R		0.12
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000048
dbscSNV1_RF	Benign	0.14
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-113818957;