rs2230205

chr19-6709693-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.1836G>A(p.Thr612=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,612,072 control chromosomes in the GnomAD database, including 19,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1934 hom., cov: 28)
  • Exomes 𝑓: 0.14 (17604 hom.)
• Consequence: C3 NM_000064.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.27

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=-0.67).
• BP6: Variant 19-6709693-C-T is Benign according to our data. Variant chr19-6709693-C-T is described in ClinVar as [Benign]. Clinvar id is 330317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C3	NM_000064.4	c.1836G>A	p.Thr612=	synonymous_variant	14/41	ENST00000245907.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C3	ENST00000245907.11	c.1836G>A	p.Thr612=	synonymous_variant	14/41	1	NM_000064.4	P1

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22262 AN: 151292 Hom.: 1932 Cov.: 28

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.435

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.132

GnomAD3 exomes AF: 0.172 AC: 43146 AN: 251408 Hom.: 4638 AF XY: 0.175 AC XY: 23748 AN XY: 135898

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.196

Gnomad EAS exome AF: 0.432

Gnomad SAS exome AF: 0.232

Gnomad FIN exome AF: 0.193

Gnomad NFE exome AF: 0.132

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.145 AC: 211286 AN: 1460662 Hom.: 17604 Cov.: 40 AF XY: 0.147 AC XY: 107013 AN XY: 726650

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.114

Gnomad4 ASJ exome AF: 0.200

Gnomad4 EAS exome AF: 0.417

Gnomad4 SAS exome AF: 0.225

Gnomad4 FIN exome AF: 0.197

Gnomad4 NFE exome AF: 0.126

Gnomad4 OTH exome AF: 0.158

GnomAD4 genome AF: 0.147 AC: 22278 AN: 151410 Hom.: 1934 Cov.: 28 AF XY: 0.153 AC XY: 11333 AN XY: 73902

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.194

Gnomad4 EAS AF: 0.435

Gnomad4 SAS AF: 0.260

Gnomad4 FIN AF: 0.192

Gnomad4 NFE AF: 0.129

Gnomad4 OTH AF: 0.129

Alfa AF: 0.135 Hom.: 2218

Bravo AF: 0.140

Asia WGS AF: 0.303 AC: 1051 AN: 3478

EpiCase AF: 0.128

EpiControl AF: 0.125

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 13, 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	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2018	- -

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 13, 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 13, 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	-0.67
Cadd	Benign	3.4
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2230205; hg19: chr19-6709704; COSMIC: COSV55575514; COSMIC: COSV55575514;