13-113164394-A-T

Variant names:

• chr13-113164394-A-T
• rs3024731
• NM_003891.3:c.374-119A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003891.3(PROZ):​c.374-119A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.724 in 1,154,872 control chromosomes in the GnomAD database, including 307,548 homozygotes. 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: 𝑓 0.67 (35069 hom., cov: 32)
  • Exomes 𝑓: 0.73 (272479 hom.)
• Consequence: PROZ NM_003891.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.33
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• protein Z deficiency

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.759 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROZ	NM_003891.3	c.374-119A>T		intron_variant	Intron 4 of 7	ENST00000375547.7	NP_003882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROZ	ENST00000375547.7	c.374-119A>T		intron_variant	Intron 4 of 7	1	NM_003891.3	ENSP00000364697.2
PROZ	ENST00000342783.5	c.440-119A>T		intron_variant	Intron 5 of 8	1		ENSP00000344458.4
PROZ	ENST00000493630.1	n.-125A>T		upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.672 AC: 101907 AN: 151700 Hom.: 35069 Cov.: 32

Gnomad AFR AF: 0.531

Gnomad AMI AF: 0.822

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.784

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.736

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.765

Gnomad OTH AF: 0.676

GnomAD4 exome AF: 0.732 AC: 733879 AN: 1003054 Hom.: 272479 AF XY: 0.726 AC XY: 371022 AN XY: 511372

African (AFR) AF: 0.519 AC: 12604 AN: 24292

American (AMR) AF: 0.613 AC: 21681 AN: 35362

Ashkenazi Jewish (ASJ) AF: 0.790 AC: 17724 AN: 22444

East Asian (EAS) AF: 0.520 AC: 17690 AN: 34000

South Asian (SAS) AF: 0.551 AC: 39234 AN: 71228

European-Finnish (FIN) AF: 0.748 AC: 29125 AN: 38914

Middle Eastern (MID) AF: 0.773 AC: 3809 AN: 4926

European-Non Finnish (NFE) AF: 0.770 AC: 559737 AN: 726770

Other (OTH) AF: 0.715 AC: 32275 AN: 45118

GnomAD4 genome AF: 0.672 AC: 101949 AN: 151818 Hom.: 35069 Cov.: 32 AF XY: 0.666 AC XY: 49381 AN XY: 74198

African (AFR) AF: 0.531 AC: 21966 AN: 41364

American (AMR) AF: 0.668 AC: 10198 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 2719 AN: 3466

East Asian (EAS) AF: 0.466 AC: 2395 AN: 5144

South Asian (SAS) AF: 0.533 AC: 2565 AN: 4812

European-Finnish (FIN) AF: 0.736 AC: 7770 AN: 10550

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.765 AC: 51938 AN: 67910

Other (OTH) AF: 0.675 AC: 1426 AN: 2112

Alfa AF: 0.707 Hom.: 3434

Bravo AF: 0.662

Asia WGS AF: 0.473 AC: 1650 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.61
DANN	Benign	0.74
PhyloP100		-1.3
Mutation Taster		=13/87	disease causing

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

Other links and lift over

dbSNP: rs3024731; hg19: chr13-113818708; COSMIC: COSV61439054; COSMIC: COSV61439054;