rs121918142
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000312.4(PROC):āc.1332G>Cā(p.Trp444Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes š: 0.0000014 ( 0 hom. )
Consequence
PROC
NM_000312.4 missense
NM_000312.4 missense
Scores
14
3
1
Clinical Significance
Conservation
PhyloP100: 9.88
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM1
?
In a domain Peptidase S1 (size 238) in uniprot entity PROC_HUMAN there are 59 pathogenic changes around while only 10 benign (86%) in NM_000312.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
?
Variant 2-127428892-G-C is Pathogenic according to our data. Variant chr2-127428892-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 657.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PROC | NM_000312.4 | c.1332G>C | p.Trp444Cys | missense_variant | 9/9 | ENST00000234071.8 | |
LOC105373608 | XR_007087228.1 | n.1041-628C>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PROC | ENST00000234071.8 | c.1332G>C | p.Trp444Cys | missense_variant | 9/9 | 1 | NM_000312.4 | P1 | |
PROC | ENST00000409048.1 | c.1434G>C | p.Trp478Cys | missense_variant | 7/7 | 5 | |||
PROC | ENST00000402125.2 | c.657G>C | p.Trp219Cys | missense_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250714Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135518
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461670Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727154
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GnomAD4 genome ? Cov.: 33
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33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Thrombophilia due to protein C deficiency, autosomal dominant Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1987 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
0.95
.;Loss of MoRF binding (P = 0.0268);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at