NM_000064.4:c.941C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000064.4(C3):c.941C>T(p.Pro314Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,613,434 control chromosomes in the GnomAD database, including 29,494 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1874 hom., cov: 31)

Exomes 𝑓: 0.19 ( 27620 hom. )

Consequence

C3
NM_000064.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.719

Publications

113 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.6191297E-4).

BP6

Variant 19-6713251-G-A is Benign according to our data. Variant chr19-6713251-G-A is described in ClinVar as Benign. ClinVar VariationId is 17057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4 link	c.941C>T	p.Pro314Leu	missense_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.941C>T	p.Pro314Leu	missense_variant	Exon 9 of 41	1	NM_000064.4	ENSP00000245907.4		P01024

Frequencies

GnomAD3 genomes

AF:

0.134

AC:

20348

AN:

151964

Hom.:

1874

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0377

Gnomad AMI

AF:

0.0658

Gnomad AMR

AF:

0.102

Gnomad ASJ

AF:

0.221

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.0923

Gnomad FIN

AF:

0.172

Gnomad MID

AF:

0.171

Gnomad NFE

AF:

0.203

Gnomad OTH

AF:

0.130

GnomAD2 exomes

AF:

0.141

AC:

35480

AN:

250810

AF XY:

0.145

show subpopulations

Gnomad AFR exome

AF:

0.0340

Gnomad AMR exome

AF:

0.0750

Gnomad ASJ exome

AF:

0.212

Gnomad EAS exome

AF:

0.000707

Gnomad FIN exome

AF:

0.166

Gnomad NFE exome

AF:

0.200

Gnomad OTH exome

AF:

0.158

GnomAD4 exome

AF:

0.185

AC:

270924

AN:

1461352

Hom.:

27620

Cov.:

AF XY:

0.183

AC XY:

133204

AN XY:

726968

show subpopulations

African (AFR)

AF:

0.0313

AC:

1047

AN:

33480

American (AMR)

AF:

0.0767

AC:

3430

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.216

AC:

5647

AN:

26134

East Asian (EAS)

AF:

0.000579

AC:

AN:

39700

South Asian (SAS)

AF:

0.101

AC:

8677

AN:

86252

European-Finnish (FIN)

AF:

0.172

AC:

9141

AN:

53000

Middle Eastern (MID)

AF:

0.135

AC:

780

AN:

5768

European-Non Finnish (NFE)

AF:

0.208

AC:

231454

AN:

1111920

Other (OTH)

AF:

0.178

AC:

10725

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

12471

24941

37412

49882

62353

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7834

15668

23502

31336

39170

<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:

0.134

AC:

20349

AN:

152082

Hom.:

1874

Cov.:

AF XY:

0.131

AC XY:

9733

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0376

AC:

1562

AN:

41528

American (AMR)

AF:

0.102

AC:

1560

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.221

AC:

765

AN:

3464

East Asian (EAS)

AF:

0.000966

AC:

AN:

5178

South Asian (SAS)

AF:

0.0935

AC:

451

AN:

4826

European-Finnish (FIN)

AF:

0.172

AC:

1820

AN:

10554

Middle Eastern (MID)

AF:

0.173

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.203

AC:

13803

AN:

67944

Other (OTH)

AF:

0.129

AC:

272

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

849

1698

2548

3397

4246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

234

468

702

936

1170

<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:

0.177

Hom.:

5805

Bravo

AF:

0.124

ESP6500AA

AF:

0.0402

AC:

177

ESP6500EA

AF:

0.205

AC:

1760

ExAC

AF:

0.143

AC:

17319

Asia WGS

AF:

0.0490

AC:

171

AN:

3478

EpiCase

AF:

0.199

EpiControl

AF:

0.197

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30131807, 19168221, 24736606, 24036950, 21784901, 25688879) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

C3 POLYMORPHISM, HAV 4-1 PLUS/MINUS TYPE

Benign:1

Oct 01, 1990

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Inborn genetic diseases

Benign:1

Jan 23, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Age related macular degeneration 9

Benign:1

Apr 27, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Atypical hemolytic-uremic syndrome with C3 anomaly

Benign:1

Apr 27, 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. -

Focal segmental glomerulosclerosis

Benign:1

Sep 27, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Complement component 3 deficiency

Benign:1

Apr 27, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.086

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.58

MetaRNN

Benign

0.00086

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

0.72

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.0

REVEL

Benign

0.020

Sift

Uncertain

0.028

Sift4G

Benign

0.11

Polyphen

0.23

Vest4

0.022

MPC

0.60

ClinPred

0.0081

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

gMVP

0.68

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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