19-6710771-G-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.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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -5.05

Publications

24 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=-0.92).

BP6

Variant 19-6710771-G-T is Benign according to our data. Variant chr19-6710771-G-T is described in ClinVar as Benign. ClinVar VariationId is 330324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000064.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	NM_000064.4	MANE Select	c.1554C>A	p.Pro518Pro	synonymous	Exon 13 of 41	NP_000055.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
C3	ENST00000245907.11	TSL:1 MANE Select	c.1554C>A	p.Pro518Pro	synonymous	Exon 13 of 41	ENSP00000245907.4
C3	ENST00000695654.1		c.678C>A	p.Pro226Pro	synonymous	Exon 5 of 32	ENSP00000512085.1
C3	ENST00000695652.1		c.1431C>A	p.Pro477Pro	synonymous	Exon 13 of 29	ENSP00000512083.1

Frequencies

GnomAD3 genomes

AF:

0.120

AC:

18290

AN:

152154

Hom.:

1499

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.126

AC:

31605

AN:

251110

AF XY:

0.129

show subpopulations

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 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.:

AF XY:

0.163

AC XY:

118460

AN XY:

727044

show subpopulations

African (AFR)

AF:

0.0287

AC:

960

AN:

33480

American (AMR)

AF:

0.0701

AC:

3136

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.155

AC:

4059

AN:

26134

East Asian (EAS)

AF:

0.000554

AC:

AN:

39700

South Asian (SAS)

AF:

0.0882

AC:

7604

AN:

86258

European-Finnish (FIN)

AF:

0.147

AC:

7827

AN:

53084

Middle Eastern (MID)

AF:

0.113

AC:

650

AN:

5768

European-Non Finnish (NFE)

AF:

0.186

AC:

207047

AN:

1111894

Other (OTH)

AF:

0.156

AC:

9414

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

11298

22597

33895

45194

56492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7072

14144

21216

28288

35360

<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:

0.120

AC:

18290

AN:

152272

Hom.:

1499

Cov.:

AF XY:

0.116

AC XY:

8673

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0343

AC:

1424

AN:

41576

American (AMR)

AF:

0.0954

AC:

1460

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.158

AC:

549

AN:

3472

East Asian (EAS)

AF:

0.000965

AC:

AN:

5180

South Asian (SAS)

AF:

0.0808

AC:

390

AN:

4826

European-Finnish (FIN)

AF:

0.146

AC:

1546

AN:

10608

Middle Eastern (MID)

AF:

0.139

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.185

AC:

12563

AN:

67978

Other (OTH)

AF:

0.119

AC:

252

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

807

1614

2421

3228

4035

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

214

428

642

856

1070

<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:

0.155

Hom.:

3823

Bravo

AF:

0.111

Asia WGS

AF:

0.0440

AC:

155

AN:

3478

EpiCase

AF:

0.180

EpiControl

AF:

0.178

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Age related macular degeneration 9 (1)

Atypical hemolytic-uremic syndrome with C3 anomaly (1)

Atypical hemolytic-uremic syndrome;C3151071:Complement component 3 deficiency;C4055342:C3 glomerulonephritis (1)

Complement component 3 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.43

(source)

DANN

Benign

0.54

PhyloP100

-5.1

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)

0.0

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over