rs7951
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_000064.4(C3):c.4311C>T(p.Ala1437=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0784 in 1,613,528 control chromosomes in the GnomAD database, including 5,204 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.086 ( 574 hom., cov: 32)
Exomes 𝑓: 0.078 ( 4630 hom. )
Consequence
C3
NM_000064.4 synonymous
NM_000064.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.297
Genes affected
C3 (HGNC:1318): (complement C3) Complement component C3 plays a central role in the activation of complement system. Its activation is required for both classical and alternative complement activation pathways. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form the mature protein, which is then further processed to generate numerous peptide products. The C3a peptide, also known as the C3a anaphylatoxin, modulates inflammation and possesses antimicrobial activity. Mutations in this gene are associated with atypical hemolytic uremic syndrome and age-related macular degeneration in human patients. [provided by RefSeq, Nov 2015]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 19-6681980-G-A is Benign according to our data. Variant chr19-6681980-G-A is described in ClinVar as [Benign]. Clinvar id is 330285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6681980-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-0.297 with no splicing effect.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0928 is higher than 0.05.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| C3 | NM_000064.4 | c.4311C>T | p.Ala1437= | synonymous_variant | 35/41 | ENST00000245907.11 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| C3 | ENST00000245907.11 | c.4311C>T | p.Ala1437= | synonymous_variant | 35/41 | 1 | NM_000064.4 | P1 |
Frequencies
GnomAD3 genomes 0.0856 AC: 13013AN: 152100Hom.: 568 Cov.: 32
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GnomAD3 exomes AF: 0.0840 AC: 21130AN: 251496Hom.: 975 AF XY: 0.0848 AC XY: 11528AN XY: 135922
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GnomAD4 exome AF: 0.0777 AC: 113483AN: 1461310Hom.: 4630 Cov.: 31 AF XY: 0.0785 AC XY: 57079AN XY: 727008
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GnomAD4 genome 0.0857 AC: 13051AN: 152218Hom.: 574 Cov.: 32 AF XY: 0.0869 AC XY: 6465AN XY: 74436
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ClinVar
Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
| Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2018 | - - |
Age related macular degeneration 9 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Atypical hemolytic-uremic syndrome with C3 anomaly Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Complement component 3 deficiency Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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