rs7951

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.4311C>T(p.Ala1437Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0784 in 1,613,528 control chromosomes in the GnomAD database, including 5,204 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.086 ( 574 hom., cov: 32)

Exomes 𝑓: 0.078 ( 4630 hom. )

Consequence

C3
NM_000064.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.297

Publications

28 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:

ENSG00000297005 (HGNC:):

ENSG00000297005 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=-0.81).

BP6

Variant 19-6681980-G-A is Benign according to our data. Variant chr19-6681980-G-A is described in ClinVar as Benign. ClinVar VariationId is 330285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.297 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0928 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4 link	c.4311C>T	p.Ala1437Ala	synonymous_variant	Exon 35 of 41	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11 link	c.4311C>T	p.Ala1437Ala	synonymous_variant	Exon 35 of 41	1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes

AF:

0.0856

AC:

13013

AN:

152100

Hom.:

568

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0947

Gnomad AMI

AF:

0.116

Gnomad AMR

AF:

0.0738

Gnomad ASJ

AF:

0.0936

Gnomad EAS

AF:

0.0975

Gnomad SAS

AF:

0.0960

Gnomad FIN

AF:

0.109

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0768

Gnomad OTH

AF:

0.0778

GnomAD2 exomes

AF:

0.0840

AC:

21130

AN:

251496

AF XY:

0.0848

show subpopulations

Gnomad AFR exome

AF:

0.0955

Gnomad AMR exome

AF:

0.0559

Gnomad ASJ exome

AF:

0.0912

Gnomad EAS exome

AF:

0.105

Gnomad FIN exome

AF:

0.121

Gnomad NFE exome

AF:

0.0768

Gnomad OTH exome

AF:

0.0847

GnomAD4 exome

AF:

0.0777

AC:

113483

AN:

1461310

Hom.:

4630

Cov.:

AF XY:

0.0785

AC XY:

57079

AN XY:

727008

show subpopulations

African (AFR)

AF:

0.0928

AC:

3107

AN:

33470

American (AMR)

AF:

0.0578

AC:

2587

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0939

AC:

2453

AN:

26132

East Asian (EAS)

AF:

0.0927

AC:

3681

AN:

39696

South Asian (SAS)

AF:

0.0951

AC:

8201

AN:

86236

European-Finnish (FIN)

AF:

0.118

AC:

6326

AN:

53420

Middle Eastern (MID)

AF:

0.0839

AC:

483

AN:

5756

European-Non Finnish (NFE)

AF:

0.0735

AC:

81721

AN:

1111494

Other (OTH)

AF:

0.0815

AC:

4924

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

5789

11578

17366

23155

28944

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3076

6152

9228

12304

15380

<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:

0.0857

AC:

13051

AN:

152218

Hom.:

574

Cov.:

AF XY:

0.0869

AC XY:

6465

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0953

AC:

3958

AN:

41536

American (AMR)

AF:

0.0738

AC:

1128

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0936

AC:

325

AN:

3472

East Asian (EAS)

AF:

0.0970

AC:

502

AN:

5176

South Asian (SAS)

AF:

0.0961

AC:

463

AN:

4820

European-Finnish (FIN)

AF:

0.109

AC:

1157

AN:

10606

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0768

AC:

5222

AN:

68004

Other (OTH)

AF:

0.0808

AC:

171

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

615

1230

1844

2459

3074

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

288

432

576

720

<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:

0.0774

Hom.:

755

Bravo

AF:

0.0830

Asia WGS

AF:

0.0870

AC:

304

AN:

3478

EpiCase

AF:

0.0747

EpiControl

AF:

0.0757

ClinVar

Significance: Benign

Submissions summary: Benign:6

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

- -

Nov 10, 2018

GeneDx

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:1

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. -

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

Complement component 3 deficiency

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

-0.81

CADD

Benign

2.7

(source)

DANN

Benign

0.44

PhyloP100

-0.30

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.020

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