rs147859257

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_000064.4(C3):c.463A>C(p.Lys155Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00379 in 1,614,084 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 18 hom. )

Consequence

C3
NM_000064.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:5O:1

Conservation

PhyloP100: -0.762

Publications

70 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 -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000064.4

BP4

Computational evidence support a benign effect (MetaRNN=0.010331094).

BP6

Variant 19-6718135-T-G is Benign according to our data. Variant chr19-6718135-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 92162.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00239 (364/152206) while in subpopulation NFE AF = 0.00446 (303/67988). AF 95% confidence interval is 0.00404. There are 0 homozygotes in GnomAd4. There are 156 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 18 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4 link	c.463A>C	p.Lys155Gln	missense_variant	Exon 4 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.463A>C	p.Lys155Gln	missense_variant	Exon 4 of 41	1	NM_000064.4	ENSP00000245907.4		P01024

Frequencies

GnomAD3 genomes

AF:

0.00239

AC:

364

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00446

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00279

AC:

702

AN:

251454

AF XY:

0.00274

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000832

Gnomad NFE exome

AF:

0.00564

Gnomad OTH exome

AF:

0.00293

GnomAD4 exome

AF:

0.00394

AC:

5761

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00381

AC XY:

2772

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

33480

American (AMR)

AF:

0.000581

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00127

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00492

AC:

5473

AN:

1112006

Other (OTH)

AF:

0.00262

AC:

158

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

349

699

1048

1398

1747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

202

404

606

808

1010

<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:

0.00239

AC:

364

AN:

152206

Hom.:

Cov.:

AF XY:

0.00210

AC XY:

156

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.000506

AC:

AN:

41526

American (AMR)

AF:

0.000850

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000943

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00446

AC:

303

AN:

67988

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00446

Hom.:

Bravo

AF:

0.00230

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00430

AC:

ExAC

AF:

0.00336

AC:

408

EpiCase

AF:

0.00305

EpiControl

AF:

0.00326

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

C3: BP4 -

not specified

Uncertain:1

Jun 11, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Age related macular degeneration 9;C2752037:Atypical hemolytic-uremic syndrome with C3 anomaly;C3151071:Complement component 3 deficiency

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Age related macular degeneration 9

Uncertain:1

May 23, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Retinal dystrophy

Uncertain:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

C3-related disorder

Benign:1

Jan 09, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Atypical hemolytic-uremic syndrome with C3 anomaly

Benign:1

May 23, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Complement component 3 deficiency

Benign:1

May 23, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

MACULAR DEGENERATION, AGE-RELATED, 9, SUSCEPTIBILITY TO

Other:1

Nov 01, 2013

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.14

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.70

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.2

PhyloP100

-0.76

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.94

REVEL

Benign

0.067

Sift

Benign

0.47

Sift4G

Benign

0.55

Polyphen

0.12

Vest4

0.14

MVP

0.79

MPC

0.64

ClinPred

0.014

GERP RS

1.3

Varity_R

0.59

gMVP

0.75

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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