rs3024778

chr13-113160151-G-Achr13-113160151-G-Cchr13-113160151-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003891.3(PROZ):c.208G>A(p.Glu70Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E70Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PROZ NM_003891.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.30

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROZ	NM_003891.3	c.208G>A	p.Glu70Lys	missense_variant	2/8	ENST00000375547.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROZ	ENST00000375547.7	c.208G>A	p.Glu70Lys	missense_variant	2/8	1	NM_003891.3	P2
PROZ	ENST00000342783.5	c.274G>A	p.Glu92Lys	missense_variant	3/9	1		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Uncertain	23
Dann	Pathogenic	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.74
MutPred		0.96		.;Gain of methylation at E70 (P = 0.0062);
MVP		1.0
MPC		0.65
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.74
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3024778; hg19: chr13-113814465; COSMIC: COSV104653216; COSMIC: COSV104653216;