rs3024772

Variant names:

• chr13-113171786-G-A
• rs3024772
• NM_003891.3:c.884G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-113171786-G-A
• chr13-113171786-G-C
• chr13-113171786-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003891.3(PROZ):​c.884G>A​(p.Arg295His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0299 in 1,612,768 control chromosomes in the GnomAD database, including 877 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.023 (63 hom., cov: 32)
  • Exomes 𝑓: 0.031 (814 hom.)
• Consequence: PROZ NM_003891.3 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.210
• Publications: 15 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]

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]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023902655).
• BP6: Variant 13-113171786-G-A is Benign according to our data. Variant chr13-113171786-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3056128.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0232 (3539/152286) while in subpopulation NFE AF = 0.0367 (2497/68004). AF 95% confidence interval is 0.0355. There are 63 homozygotes in GnomAd4. There are 1637 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 63 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003891.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROZ	NM_003891.3	MANE Select	c.884G>A	p.Arg295His	missense	Exon 8 of 8	NP_003882.1	P22891-1
	PROZ	NM_001256134.2		c.950G>A	p.Arg317His	missense	Exon 9 of 9	NP_001243063.1	P22891-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROZ	ENST00000375547.7	TSL:1 MANE Select	c.884G>A	p.Arg295His	missense	Exon 8 of 8	ENSP00000364697.2	P22891-1
	PROZ	ENST00000342783.5	TSL:1	c.950G>A	p.Arg317His	missense	Exon 9 of 9	ENSP00000344458.4	P22891-2
	PROZ	ENST00000906454.1		c.1031G>A	p.Arg344His	missense	Exon 10 of 10	ENSP00000576513.1

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3539 AN: 152168 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.00591

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.0374

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.0171

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0367

Gnomad OTH AF: 0.0273

GnomAD2 exomes AF: 0.0245 AC: 6143 AN: 250738 AF XY: 0.0252

Gnomad AFR exome AF: 0.00617

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.0409

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0202

Gnomad NFE exome AF: 0.0379

Gnomad OTH exome AF: 0.0254

GnomAD4 exome AF: 0.0305 AC: 44606 AN: 1460482 Hom.: 814 Cov.: 31 AF XY: 0.0300 AC XY: 21789 AN XY: 726356

African (AFR) AF: 0.00514 AC: 172 AN: 33460

American (AMR) AF: 0.0158 AC: 705 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 956 AN: 26120

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39684

South Asian (SAS) AF: 0.00821 AC: 708 AN: 86240

European-Finnish (FIN) AF: 0.0199 AC: 1054 AN: 52900

Middle Eastern (MID) AF: 0.0245 AC: 141 AN: 5766

European-Non Finnish (NFE) AF: 0.0353 AC: 39245 AN: 1111242

Other (OTH) AF: 0.0269 AC: 1623 AN: 60358

GnomAD4 genome AF: 0.0232 AC: 3539 AN: 152286 Hom.: 63 Cov.: 32 AF XY: 0.0220 AC XY: 1637 AN XY: 74452

African (AFR) AF: 0.00587 AC: 244 AN: 41574

American (AMR) AF: 0.0204 AC: 312 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0374 AC: 130 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4826

European-Finnish (FIN) AF: 0.0171 AC: 182 AN: 10616

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0367 AC: 2497 AN: 68004

Other (OTH) AF: 0.0270 AC: 57 AN: 2110

Alfa AF: 0.0331 Hom.: 409

Bravo AF: 0.0232

TwinsUK AF: 0.0326 AC: 121

ALSPAC AF: 0.0371 AC: 143

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0372 AC: 320

ExAC AF: 0.0254 AC: 3079

Asia WGS AF: 0.00520 AC: 19 AN: 3478

EpiCase AF: 0.0371

EpiControl AF: 0.0409

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PROZ-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.21
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.27
Sift	Benign	0.087	T
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.024
MPC		0.17
ClinPred		0.019	T
GERP RS		0.82
Varity_R		0.066
gMVP		0.44
Mutation Taster		=93/7	polymorphism (auto)

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: rs3024772; hg19: chr13-113826100; COSMIC: COSV61439929; COSMIC: COSV61439929;