NM_000312.4:c.446A>G

Variant names:

• chr2-127423319-A-G
• rs121918159
• NM_000312.4:c.446A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H149P) has been classified as Pathogenic.

• 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
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000312.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-127423319-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 679.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 0.88339 (below the threshold of 3.09). Trascript score misZ: 1.6095 (below the threshold of 3.09). GenCC associations: The gene is linked to thrombophilia due to protein C deficiency, autosomal dominant, thrombophilia due to protein C deficiency, autosomal recessive, hereditary thrombophilia due to congenital protein C deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000312.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROC	NM_000312.4	MANE Select	c.446A>G	p.His149Arg	missense	Exon 6 of 9	NP_000303.1
	PROC	NM_001375607.1		c.632A>G	p.His211Arg	missense	Exon 5 of 8	NP_001362536.1
	PROC	NM_001375602.1		c.629A>G	p.His210Arg	missense	Exon 6 of 9	NP_001362531.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROC	ENST00000234071.8	TSL:1 MANE Select	c.446A>G	p.His149Arg	missense	Exon 6 of 9	ENSP00000234071.4
	PROC	ENST00000409048.1	TSL:5	c.548A>G	p.His183Arg	missense	Exon 4 of 7	ENSP00000386679.1
	PROC	ENST00000402125.2	TSL:2	c.29A>G	p.His10Arg	missense	Exon 1 of 2	ENSP00000384225.2

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 v4.9

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
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.0039	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		6.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.77
Sift4G	Uncertain	0.023	D
Polyphen		0.99	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
PromoterAI		-0.066	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.99
Mutation Taster		=2/98	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: rs121918159; hg19: chr2-128180895;