chr19-6678007-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong

The NM_000064.4(C3):​c.4867G>T​(p.Gly1623Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 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 Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

C3
NM_000064.4 missense

Scores

6
10
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.15
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 Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), C3. . Gene score misZ 2.7489 (greater than the threshold 3.09). Trascript score misZ 4.431 (greater than threshold 3.09). GenCC has associacion of gene with complement component 3 deficiency, C3 glomerulonephritis, atypical hemolytic-uremic syndrome with C3 anomaly.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
C3NM_000064.4 linkuse as main transcriptc.4867G>T p.Gly1623Trp missense_variant 41/41 ENST00000245907.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
C3ENST00000245907.11 linkuse as main transcriptc.4867G>T p.Gly1623Trp missense_variant 41/411 NM_000064.4 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461892
Hom.:
0
Cov.:
35
AF XY:
0.00
AC XY:
0
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Age related macular degeneration 9 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsDec 16, 2022- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 27, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with C3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 1623 of the C3 protein (p.Gly1623Trp). -
Atypical hemolytic-uremic syndrome with C3 anomaly Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsDec 16, 2022- -
Complement component 3 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsDec 16, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Uncertain
0.072
D
BayesDel_noAF
Benign
-0.13
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.37
T
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.89
D
M_CAP
Pathogenic
0.81
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Uncertain
-0.066
T
MutationAssessor
Pathogenic
3.6
H
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-5.9
D
REVEL
Uncertain
0.50
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.64
MutPred
0.82
Gain of ubiquitination at K1624 (P = 0.0598);
MVP
0.78
MPC
1.7
ClinPred
1.0
D
GERP RS
3.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.98
gMVP
0.89

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: rs1727088882; hg19: chr19-6678018; API