NM_000064.4:c.912G>A

Variant names:

• chr19-6713280-C-T
• rs2230201
• NM_000064.4:c.912G>A

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.912G>A​(p.Arg304Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,613,380 control chromosomes in the GnomAD database, including 25,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2387 hom., cov: 31)
  • Exomes 𝑓: 0.17 (23061 hom.)
• Consequence: C3 NM_000064.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0960

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-6713280-C-T is Benign according to our data. Variant chr19-6713280-C-T is described in ClinVar as [Benign]. Clinvar id is 330332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6713280-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.096 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.426 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4	c.912G>A	p.Arg304Arg	synonymous_variant	Exon 9 of 41	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.912G>A	p.Arg304Arg	synonymous_variant	Exon 9 of 41	1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25364 AN: 151952 Hom.: 2386 Cov.: 31

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.148

GnomAD3 exomes AF: 0.192 AC: 48048 AN: 250712 Hom.: 5421 AF XY: 0.194 AC XY: 26286 AN XY: 135612

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.174

Gnomad EAS exome AF: 0.444

Gnomad SAS exome AF: 0.235

Gnomad FIN exome AF: 0.217

Gnomad NFE exome AF: 0.162

Gnomad OTH exome AF: 0.183

GnomAD4 exome AF: 0.170 AC: 248109 AN: 1461310 Hom.: 23061 Cov.: 36 AF XY: 0.172 AC XY: 124943 AN XY: 726956

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.139

Gnomad4 ASJ exome AF: 0.175

Gnomad4 EAS exome AF: 0.430

Gnomad4 SAS exome AF: 0.227

Gnomad4 FIN exome AF: 0.220

Gnomad4 NFE exome AF: 0.156

Gnomad4 OTH exome AF: 0.177

GnomAD4 genome AF: 0.167 AC: 25374 AN: 152070 Hom.: 2387 Cov.: 31 AF XY: 0.173 AC XY: 12844 AN XY: 74332

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.144

Gnomad4 ASJ AF: 0.173

Gnomad4 EAS AF: 0.442

Gnomad4 SAS AF: 0.264

Gnomad4 FIN AF: 0.217

Gnomad4 NFE AF: 0.161

Gnomad4 OTH AF: 0.145

Alfa AF: 0.159 Hom.: 2088

Bravo AF: 0.158

Asia WGS AF: 0.307 AC: 1068 AN: 3478

EpiCase AF: 0.155

EpiControl AF: 0.150

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

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	-0.87
CADD	Benign	0.94
DANN	Benign	0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2230201; hg19: chr19-6713291; COSMIC: COSV55580082; COSMIC: COSV55580082;