chr19-6677996-A-G
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1
The NM_000064.4(C3):āc.4878T>Cā(p.Thr1626=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000453 in 1,613,922 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.0025 ( 0 hom., cov: 32)
Exomes š: 0.00024 ( 1 hom. )
Consequence
C3
NM_000064.4 synonymous
NM_000064.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.59
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 -16 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.73).
BP6
Variant 19-6677996-A-G is Benign according to our data. Variant chr19-6677996-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 789661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0025 (380/152036) while in subpopulation AFR AF= 0.00847 (351/41462). AF 95% confidence interval is 0.00774. There are 0 homozygotes in gnomad4. There are 186 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
C3 | NM_000064.4 | c.4878T>C | p.Thr1626= | synonymous_variant | 41/41 | ENST00000245907.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
C3 | ENST00000245907.11 | c.4878T>C | p.Thr1626= | synonymous_variant | 41/41 | 1 | NM_000064.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00244 AC: 370AN: 151918Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000648 AC: 163AN: 251492Hom.: 0 AF XY: 0.000405 AC XY: 55AN XY: 135918
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GnomAD4 exome AF: 0.000240 AC: 351AN: 1461886Hom.: 1 Cov.: 35 AF XY: 0.000209 AC XY: 152AN XY: 727244
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GnomAD4 genome AF: 0.00250 AC: 380AN: 152036Hom.: 0 Cov.: 32 AF XY: 0.00250 AC XY: 186AN XY: 74322
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 26, 2019 | - - |
Kidney disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Feb 01, 2018 | - - |
Age related macular degeneration 9;C2752037:Atypical hemolytic-uremic syndrome with C3 anomaly;C3151071:Complement component 3 deficiency Benign:1
Benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 20, 2021 | - - |
Age related macular degeneration 9 Benign:1
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
C3-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 08, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | - - |
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
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Computational scores
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Name
Calibrated prediction
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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