2-127423319-A-G

Variant names:

• chr2-127423319-A-G
• NM_000312.4:c.446A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000312.4(PROC):​c.446A>G​(p.His149Arg) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 36)
• Consequence: PROC NM_000312.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.85

Genes affected

PROC (HGNC:9451): (protein C, inactivator of coagulation factors Va and VIIIa) This gene encodes a vitamin K-dependent plasma glycoprotein. The encoded protein is cleaved to its activated form by the thrombin-thrombomodulin complex. This activated form contains a serine protease domain and functions in degradation of the activated forms of coagulation factors V and VIII. Mutations in this gene have been associated with thrombophilia due to protein C deficiency, neonatal purpura fulminans, and recurrent venous thrombosis.[provided by RefSeq, Dec 2009]

MIR4783 (HGNC:41874): (microRNA 4783) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROC	NM_000312.4	c.446A>G	p.His149Arg	missense_variant	Exon 6 of 9	ENST00000234071.8	NP_000303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROC	ENST00000234071.8	c.446A>G	p.His149Arg	missense_variant	Exon 6 of 9	1	NM_000312.4	ENSP00000234071.4

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD4 exome Cov.: 76

GnomAD4 genome Cov.: 36

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Thrombophilia due to protein C deficiency, autosomal dominant Uncertain:1

Feb 23, 2023

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.77; 3Cnet: 0.75). A different missense change at the same codon (p.His149Pro) has been reported to be associated with PROC related disorder (ClinVar ID: VCV000000679 / PMID: 10805275). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Benign	0.85
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D;T
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.0039	D
MutationAssessor	Pathogenic	3.4	M;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Pathogenic	0.77
Sift4G	Uncertain	0.023	D;D
Polyphen		0.99	D;D
Vest4		0.57
MutPred		0.62		.;Gain of relative solvent accessibility (P = 0.1259);
MVP		0.97
MPC		0.66
ClinPred		0.95	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-128180895;