Genetic Variant PROZ:c.573+79G>T (chr13-113165199-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003891.3(PROZ):c.573+79G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000775 in 1,291,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

PROZ
NM_003891.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.30

Publications

23 publications found

Variant links:

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 links:

PCID2 (HGNC:25653): (PCI domain containing 2) This gene encodes a component of the TREX-2 complex (transcription and export complex 2), which regulates mRNA export from the nucleus. This protein regulates expression of Mad2 mitotic arrest deficient-like 1, a cell division checkpoint protein. This protein also interacts with and stabilizes Brca2 (breast cancer 2) protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

PCID2 links:

ENSG00000269125 (HGNC:):

ENSG00000269125 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROZ	NM_003891.3 link	c.573+79G>T		intron_variant	Intron 6 of 7	ENST00000375547.7	NP_003882.1	P22891-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PROZ	ENST00000375547.7 link	c.573+79G>T	intron_variant	Intron 6 of 7	1	NM_003891.3	ENSP00000364697.2	P22891-1
PROZ	ENST00000342783.5 link	c.639+79G>T	intron_variant	Intron 7 of 8	1		ENSP00000344458.4	P22891-2
PROZ	ENST00000493630.1 link	n.194+79G>T	intron_variant	Intron 2 of 4	5
ENSG00000269125	ENST00000600642.1 link	n.-16C>A	upstream_gene_variant		6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.75e-7

AC:

AN:

1291108

Hom.:

Cov.:

AF XY:

0.00000154

AC XY:

AN XY:

648938

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30044

American (AMR)

AF:

0.00

AC:

AN:

41324

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24980

East Asian (EAS)

AF:

0.00

AC:

AN:

38326

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81514

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38648

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5060

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

976078

Other (OTH)

AF:

0.00

AC:

AN:

55134

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.10

(source)

DANN

Benign

0.46

PhyloP100

-1.3

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over