13-113171786-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003891.3(PROZ):​c.884G>T​(p.Arg295Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,500 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R295H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PROZ NM_003891.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.210
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>T	p.Arg295Leu	missense	Exon 8 of 8	NP_003882.1	P22891-1
	PROZ	NM_001256134.2		c.950G>T	p.Arg317Leu	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>T	p.Arg295Leu	missense	Exon 8 of 8	ENSP00000364697.2	P22891-1
	PROZ	ENST00000342783.5	TSL:1	c.950G>T	p.Arg317Leu	missense	Exon 9 of 9	ENSP00000344458.4	P22891-2
	PROZ	ENST00000906454.1		c.1031G>T	p.Arg344Leu	missense	Exon 10 of 10	ENSP00000576513.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460500 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726372

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111258

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	12
DANN	Benign	0.89
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.081	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.21
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.30
Sift	Benign	0.13	T
Sift4G	Benign	0.33	T
Polyphen		0.82	P
Vest4		0.13
MutPred		0.84		Loss of MoRF binding (P = 0.0587)
MVP		0.88
MPC		0.21
ClinPred		0.57	D
GERP RS		0.82
Varity_R		0.22
gMVP		0.58
Mutation Taster		=89/11	polymorphism

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;