rs428453

Positions:

• chr19-6702146-C-G
• chr19-6702146-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.138

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 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/exons	MANE	Protein	UniProt
C3	NM_000064.4	c.2421G>C	p.Val807Val	synonymous_variant	19/41	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.2421G>C	p.Val807Val	synonymous_variant	19/41	1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.659 AC: 100195 AN: 151948 Hom.: 33391 Cov.: 32

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

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

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

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

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Age related macular degeneration 9 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Complement component 3 deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 12, 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

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

Other links and lift over

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