rs121909588
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_001735.3(C5):c.4426C>T(p.Arg1476Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000694 in 1,613,830 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000060 ( 0 hom. )
Consequence
C5
NM_001735.3 stop_gained
NM_001735.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 2.88
Genes affected
C5 (HGNC:1331): (complement C5) This gene encodes a component of the complement system, a part of the innate immune system that plays an important role in inflammation, host homeostasis, and host defense against pathogens. The encoded preproprotein is proteolytically processed to generate multiple protein products, including the C5 alpha chain, C5 beta chain, C5a anaphylatoxin and C5b. The C5 protein is comprised of the C5 alpha and beta chains, which are linked by a disulfide bridge. Cleavage of the alpha chain by a convertase enzyme results in the formation of the C5a anaphylatoxin, which possesses potent spasmogenic and chemotactic activity, and the C5b macromolecular cleavage product, a subunit of the membrane attack complex (MAC). Mutations in this gene cause complement component 5 deficiency, a disease characterized by recurrent bacterial infections. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 9-120962749-G-A is Pathogenic according to our data. Variant chr9-120962749-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
C5 | NM_001735.3 | c.4426C>T | p.Arg1476Ter | stop_gained | 36/41 | ENST00000223642.3 | |
C5 | NM_001317163.2 | c.4444C>T | p.Arg1482Ter | stop_gained | 36/41 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
C5 | ENST00000223642.3 | c.4426C>T | p.Arg1476Ter | stop_gained | 36/41 | 1 | NM_001735.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000158 AC: 24AN: 152152Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000756 AC: 19AN: 251270Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135784
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GnomAD4 exome AF: 0.0000602 AC: 88AN: 1461678Hom.: 0 Cov.: 31 AF XY: 0.0000578 AC XY: 42AN XY: 727164
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GnomAD4 genome ? AF: 0.000158 AC: 24AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74328
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Complement component 5 deficiency Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | May 15, 1995 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 07, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Complement component 5 deficiency;C3810402:Eculizumab, poor response to Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 26, 2022 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change creates a premature translational stop signal (p.Arg1476*) in the C5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in C5 are known to be pathogenic (PMID: 7730648, 19414197, 27026170). This variant is present in population databases (rs121909588, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with complement component 5 (C5) deficiency (PMID: 7730648). This variant is also known as p.Arg1458*. ClinVar contains an entry for this variant (Variation ID: 17051). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
GERP RS
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