19-6677978-G-A

Variant names:

• chr19-6677978-G-A
• rs17030
• NM_000064.4:c.4896C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000064.4(C3):​c.4896C>T​(p.Pro1632Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 1,613,702 control chromosomes in the GnomAD database, including 217,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (19802 hom., cov: 31)
  • Exomes 𝑓: 0.52 (197895 hom.)
• Consequence: C3 NM_000064.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -6.82

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]

ENSG00000297005 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-6677978-G-A is Benign according to our data. Variant chr19-6677978-G-A is described in ClinVar as [Benign]. Clinvar id is 330270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6677978-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-6.82 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4	c.4896C>T	p.Pro1632Pro	synonymous_variant	Exon 41 of 41	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.4896C>T	p.Pro1632Pro	synonymous_variant	Exon 41 of 41	1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.509 AC: 77195 AN: 151750 Hom.: 19799 Cov.: 31

Gnomad AFR AF: 0.492

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.536

Gnomad SAS AF: 0.587

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.513

Gnomad OTH AF: 0.529

GnomAD2 exomes AF: 0.524 AC: 131855 AN: 251460 AF XY: 0.527

Gnomad AFR exome AF: 0.494

Gnomad AMR exome AF: 0.511

Gnomad ASJ exome AF: 0.464

Gnomad EAS exome AF: 0.548

Gnomad FIN exome AF: 0.499

Gnomad NFE exome AF: 0.521

Gnomad OTH exome AF: 0.516

GnomAD4 exome AF: 0.519 AC: 758850 AN: 1461834 Hom.: 197895 Cov.: 59 AF XY: 0.521 AC XY: 378656 AN XY: 727218

African (AFR) AF: 0.495 AC: 16567 AN: 33480

American (AMR) AF: 0.518 AC: 23155 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 11955 AN: 26136

East Asian (EAS) AF: 0.518 AC: 20548 AN: 39698

South Asian (SAS) AF: 0.592 AC: 51031 AN: 86256

European-Finnish (FIN) AF: 0.500 AC: 26726 AN: 53414

Middle Eastern (MID) AF: 0.529 AC: 3051 AN: 5768

European-Non Finnish (NFE) AF: 0.517 AC: 574471 AN: 1111966

Other (OTH) AF: 0.519 AC: 31346 AN: 60392

GnomAD4 genome AF: 0.508 AC: 77213 AN: 151868 Hom.: 19802 Cov.: 31 AF XY: 0.508 AC XY: 37712 AN XY: 74190

African (AFR) AF: 0.491 AC: 20323 AN: 41400

American (AMR) AF: 0.525 AC: 8003 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 1593 AN: 3472

East Asian (EAS) AF: 0.535 AC: 2736 AN: 5116

South Asian (SAS) AF: 0.586 AC: 2819 AN: 4808

European-Finnish (FIN) AF: 0.488 AC: 5160 AN: 10568

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.513 AC: 34836 AN: 67936

Other (OTH) AF: 0.528 AC: 1114 AN: 2110

Alfa AF: 0.512 Hom.: 24141

Bravo AF: 0.511

Asia WGS AF: 0.573 AC: 1995 AN: 3478

EpiCase AF: 0.519

EpiControl AF: 0.524

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Age related macular degeneration 9 Benign:2

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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

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

- -

Complement component 3 deficiency Benign:2

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. -

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 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	-0.85
CADD	Benign	0.0040
DANN	Benign	0.76
PhyloP100		-6.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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

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Other links and lift over

dbSNP: rs17030; hg19: chr19-6677989; COSMIC: COSV55570961; COSMIC: COSV55570961;