NM_000064.4:c.2863+7C>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.2863+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.639 in 1,612,156 control chromosomes in the GnomAD database, including 332,996 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 33415 hom., cov: 30)

Exomes 𝑓: 0.64 ( 299581 hom. )

Consequence

C3
NM_000064.4 splice_region, intron

Scores

Splicing: ADA: 0.0005128

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.712

Publications

19 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 (BayesDel_noAF=-0.87).

BP6

Variant 19-6696586-G-A is Benign according to our data. Variant chr19-6696586-G-A is described in ClinVar as Benign. ClinVar VariationId is 330297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4 link	c.2863+7C>T		splice_region_variant, intron_variant	Intron 22 of 40	ENST00000245907.11	NP_000055.2	P01024V9HWA9B4DR57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11 link	c.2863+7C>T		splice_region_variant, intron_variant	Intron 22 of 40	1	NM_000064.4	ENSP00000245907.4		P01024

Frequencies

GnomAD3 genomes

AF:

0.660

AC:

100070

AN:

151660

Hom.:

33373

Cov.:

show subpopulations

Gnomad AFR

AF:

0.706

Gnomad AMI

AF:

0.443

Gnomad AMR

AF:

0.736

Gnomad ASJ

AF:

0.613

Gnomad EAS

AF:

0.842

Gnomad SAS

AF:

0.713

Gnomad FIN

AF:

0.569

Gnomad MID

AF:

0.674

Gnomad NFE

AF:

0.616

Gnomad OTH

AF:

0.676

GnomAD2 exomes

AF:

0.674

AC:

169368

AN:

251462

AF XY:

0.666

show subpopulations

Gnomad AFR exome

AF:

0.707

Gnomad AMR exome

AF:

0.811

Gnomad ASJ exome

AF:

0.597

Gnomad EAS exome

AF:

0.838

Gnomad FIN exome

AF:

0.566

Gnomad NFE exome

AF:

0.618

Gnomad OTH exome

AF:

0.664

GnomAD4 exome

AF:

0.637

AC:

929802

AN:

1460380

Hom.:

299581

Cov.:

AF XY:

0.637

AC XY:

462804

AN XY:

726596

show subpopulations

African (AFR)

AF:

0.714

AC:

23873

AN:

33450

American (AMR)

AF:

0.800

AC:

35791

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.593

AC:

15482

AN:

26126

East Asian (EAS)

AF:

0.865

AC:

34331

AN:

39696

South Asian (SAS)

AF:

0.706

AC:

60859

AN:

86236

European-Finnish (FIN)

AF:

0.567

AC:

30261

AN:

53402

Middle Eastern (MID)

AF:

0.673

AC:

3884

AN:

5768

European-Non Finnish (NFE)

AF:

0.618

AC:

686205

AN:

1110624

Other (OTH)

AF:

0.648

AC:

39116

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

18102

36204

54307

72409

90511

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18530

37060

55590

74120

92650

<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:

0.660

AC:

100168

AN:

151776

Hom.:

33415

Cov.:

AF XY:

0.662

AC XY:

49098

AN XY:

74148

show subpopulations

African (AFR)

AF:

0.707

AC:

29237

AN:

41362

American (AMR)

AF:

0.737

AC:

11226

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.613

AC:

2125

AN:

3466

East Asian (EAS)

AF:

0.842

AC:

4349

AN:

5164

South Asian (SAS)

AF:

0.711

AC:

3425

AN:

4814

European-Finnish (FIN)

AF:

0.569

AC:

5967

AN:

10494

Middle Eastern (MID)

AF:

0.673

AC:

198

AN:

294

European-Non Finnish (NFE)

AF:

0.616

AC:

41822

AN:

67926

Other (OTH)

AF:

0.673

AC:

1416

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1663

3326

4990

6653

8316

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

806

1612

2418

3224

4030

<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:

0.636

Hom.:

45544

Bravo

AF:

0.675

Asia WGS

AF:

0.771

AC:

2680

AN:

3478

EpiCase

AF:

0.634

EpiControl

AF:

0.633

ClinVar

Significance: Benign

Submissions summary: Benign:10

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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 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. -

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 13, 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 13, 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

0.51

(source)

DANN

Benign

0.41

PhyloP100

-0.71

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00051

dbscSNV1_RF

Benign

0.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over