chr19-6713280-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0960

Publications

23 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

atypical hemolytic-uremic syndrome with C3 anomaly
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
complement component 3 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Laboratory for Molecular Medicine
C3 glomerulonephritis
Inheritance: AD Classification: MODERATE Submitted by: ClinGen

C3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 330332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 link	c.912G>A	p.Arg304Arg	synonymous_variant	Exon 9 of 41	ENST00000245907.11	NP_000055.2	P01024V9HWA9B4DR57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11 link	c.912G>A	p.Arg304Arg	synonymous_variant	Exon 9 of 41	1	NM_000064.4	ENSP00000245907.4		P01024

Frequencies

GnomAD3 genomes

AF:

0.167

AC:

25364

AN:

151952

Hom.:

2386

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.192

AC:

48048

AN:

250712

AF XY:

0.194

show subpopulations

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 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.:

AF XY:

0.172

AC XY:

124943

AN XY:

726956

show subpopulations

African (AFR)

AF:

0.125

AC:

4178

AN:

33480

American (AMR)

AF:

0.139

AC:

6217

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.175

AC:

4572

AN:

26132

East Asian (EAS)

AF:

0.430

AC:

17067

AN:

39690

South Asian (SAS)

AF:

0.227

AC:

19540

AN:

86254

European-Finnish (FIN)

AF:

0.220

AC:

11676

AN:

53008

Middle Eastern (MID)

AF:

0.130

AC:

751

AN:

5768

European-Non Finnish (NFE)

AF:

0.156

AC:

173414

AN:

1111892

Other (OTH)

AF:

0.177

AC:

10694

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

12384

24768

37153

49537

61921

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6310

12620

18930

25240

31550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.167

AC:

25374

AN:

152070

Hom.:

2387

Cov.:

AF XY:

0.173

AC XY:

12844

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.125

AC:

5189

AN:

41478

American (AMR)

AF:

0.144

AC:

2205

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.173

AC:

599

AN:

3464

East Asian (EAS)

AF:

0.442

AC:

2275

AN:

5152

South Asian (SAS)

AF:

0.264

AC:

1269

AN:

4810

European-Finnish (FIN)

AF:

0.217

AC:

2292

AN:

10580

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.161

AC:

10921

AN:

67976

Other (OTH)

AF:

0.145

AC:

307

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1066

2132

3197

4263

5329

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

286

572

858

1144

1430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.156

Hom.:

2534

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

LINK: link

Submissions by phenotype

not provided

Benign:3

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Age related macular degeneration 9

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Complement component 3 deficiency

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.94

(source)

DANN

Benign

0.43

PhyloP100

0.096

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over