rs794729228

Positions:

• chr19-6714208-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_000064.4(C3):​c.640C>T​(p.Pro214Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: C3 NM_000064.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 5.76

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]

C3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C3	NM_000064.4	c.640C>T	p.Pro214Ser	missense_variant	6/41	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.640C>T	p.Pro214Ser	missense_variant	6/41	1	NM_000064.4	ENSP00000245907.4
C3	ENST00000695652.1	c.517C>T	p.Pro173Ser	missense_variant	6/29			ENSP00000512083.1
C3	ENST00000595577.1	n.144C>T		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Atypical hemolytic-uremic syndrome with C3 anomaly Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Mendelics

Dec 20, 2013

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2023

In 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt C3 protein function. ClinVar contains an entry for this variant (Variation ID: 202203). This missense change has been observed in individual(s) with C3-related conditions (PMID: 29888403). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 214 of the C3 protein (p.Pro214Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.44
MutPred		0.57		Loss of catalytic residue at P214 (P = 0.0492);
MVP		0.79
MPC		1.5
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.75
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs794729228; hg19: chr19-6714219;