GeneBe

rs428453

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000064.4(C3):​c.2421G>C​(p.Val807Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.638 in 1,595,750 control chromosomes in the GnomAD database, including 329,713 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 33429 hom., cov: 32)
Exomes 𝑓: 0.64 ( 296284 hom. )

Consequence

C3
NM_000064.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.138
Variant links:
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=-0.62).
BP6
Variant 19-6702146-C-G is Benign according to our data. Variant chr19-6702146-C-G is described in ClinVar as [Benign]. Clinvar id is 330305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6702146-C-G is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=0.138 with no splicing effect.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.821 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
C3NM_000064.4 linkc.2421G>C p.Val807Val synonymous_variant Exon 19 of 41 ENST00000245907.11 NP_000055.2 P01024V9HWA9B4DR57

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
C3ENST00000245907.11 linkc.2421G>C p.Val807Val synonymous_variant Exon 19 of 41 1 NM_000064.4 ENSP00000245907.4 P01024

Frequencies

GnomAD3 genomes
AF:
0.659
AC:
100195
AN:
151948
Hom.:
33391
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.704
Gnomad AMI
AF:
0.444
Gnomad AMR
AF:
0.736
Gnomad ASJ
AF:
0.613
Gnomad EAS
AF:
0.841
Gnomad SAS
AF:
0.713
Gnomad FIN
AF:
0.569
Gnomad MID
AF:
0.674
Gnomad NFE
AF:
0.616
Gnomad OTH
AF:
0.676
GnomAD3 exomes
AF:
0.674
AC:
168682
AN:
250406
Hom.:
57984
AF XY:
0.666
AC XY:
90270
AN XY:
135440
show subpopulations
Gnomad AFR exome
AF:
0.705
Gnomad AMR exome
AF:
0.811
Gnomad ASJ exome
AF:
0.597
Gnomad EAS exome
AF:
0.838
Gnomad SAS exome
AF:
0.710
Gnomad FIN exome
AF:
0.563
Gnomad NFE exome
AF:
0.619
Gnomad OTH exome
AF:
0.664
GnomAD4 exome
AF:
0.636
AC:
918576
AN:
1443684
Hom.:
296284
Cov.:
30
AF XY:
0.637
AC XY:
458040
AN XY:
719452
show subpopulations
Gnomad4 AFR exome
AF:
0.711
Gnomad4 AMR exome
AF:
0.800
Gnomad4 ASJ exome
AF:
0.592
Gnomad4 EAS exome
AF:
0.865
Gnomad4 SAS exome
AF:
0.706
Gnomad4 FIN exome
AF:
0.565
Gnomad4 NFE exome
AF:
0.617
Gnomad4 OTH exome
AF:
0.648
GnomAD4 genome
AF:
0.660
AC:
100290
AN:
152066
Hom.:
33429
Cov.:
32
AF XY:
0.662
AC XY:
49190
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.705
Gnomad4 AMR
AF:
0.736
Gnomad4 ASJ
AF:
0.613
Gnomad4 EAS
AF:
0.842
Gnomad4 SAS
AF:
0.712
Gnomad4 FIN
AF:
0.569
Gnomad4 NFE
AF:
0.616
Gnomad4 OTH
AF:
0.672
Alfa
AF:
0.635
Hom.:
20753
Bravo
AF:
0.675
Asia WGS
AF:
0.765
AC:
2659
AN:
3478
EpiCase
AF:
0.635
EpiControl
AF:
0.633

ClinVar

Significance: Benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Age related macular degeneration 9 Benign:2
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jul 14, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Complement component 3 deficiency Benign:2
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jul 14, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Atypical hemolytic-uremic syndrome with C3 anomaly Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.62
CADD
Benign
7.2
DANN
Benign
0.69
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs428453; hg19: chr19-6702157; COSMIC: COSV55573154; COSMIC: COSV55573154; API