19-6710771-G-T

Variant names:

• chr19-6710771-G-T
• rs2230203
• NM_000064.4:c.1554C>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.1554C>A​(p.Pro518Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,613,698 control chromosomes in the GnomAD database, including 23,262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1499 hom., cov: 32)
  • Exomes 𝑓: 0.16 (21763 hom.)
• Consequence: C3 NM_000064.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -5.05

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=-0.92).
• BP6: Variant 19-6710771-G-T is Benign according to our data. Variant chr19-6710771-G-T is described in ClinVar as [Benign]. Clinvar id is 330324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6710771-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-5.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4	c.1554C>A	p.Pro518Pro	synonymous_variant	Exon 13 of 41	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.1554C>A	p.Pro518Pro	synonymous_variant	Exon 13 of 41	1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18290 AN: 152154 Hom.: 1499 Cov.: 32

Gnomad AFR AF: 0.0343

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0956

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0797

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.120

GnomAD3 exomes AF: 0.126 AC: 31605 AN: 251110 Hom.: 2543 AF XY: 0.129 AC XY: 17479 AN XY: 135834

Gnomad AFR exome AF: 0.0313

Gnomad AMR exome AF: 0.0692

Gnomad ASJ exome AF: 0.153

Gnomad EAS exome AF: 0.000653

Gnomad SAS exome AF: 0.0869

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.181

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.165 AC: 240719 AN: 1461426 Hom.: 21763 Cov.: 35 AF XY: 0.163 AC XY: 118460 AN XY: 727044

Gnomad4 AFR exome AF: 0.0287

Gnomad4 AMR exome AF: 0.0701

Gnomad4 ASJ exome AF: 0.155

Gnomad4 EAS exome AF: 0.000554

Gnomad4 SAS exome AF: 0.0882

Gnomad4 FIN exome AF: 0.147

Gnomad4 NFE exome AF: 0.186

Gnomad4 OTH exome AF: 0.156

GnomAD4 genome AF: 0.120 AC: 18290 AN: 152272 Hom.: 1499 Cov.: 32 AF XY: 0.116 AC XY: 8673 AN XY: 74452

Gnomad4 AFR AF: 0.0343

Gnomad4 AMR AF: 0.0954

Gnomad4 ASJ AF: 0.158

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.0808

Gnomad4 FIN AF: 0.146

Gnomad4 NFE AF: 0.185

Gnomad4 OTH AF: 0.119

Alfa AF: 0.158 Hom.: 2704

Bravo AF: 0.111

Asia WGS AF: 0.0440 AC: 155 AN: 3478

EpiCase AF: 0.180

EpiControl AF: 0.178

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jun 09, 2021

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

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Age related macular degeneration 9 Benign:1

Jan 13, 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. -

Atypical hemolytic-uremic syndrome with C3 anomaly Benign:1

Jan 13, 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. -

Complement component 3 deficiency Benign:1

Jan 13, 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	-0.92
CADD	Benign	0.43
DANN	Benign	0.54
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: rs2230203; hg19: chr19-6710782; COSMIC: COSV55573800; COSMIC: COSV55573800;