chr19-6697395-A-G

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.2745T>C(p.Ala915Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.768 in 1,613,598 control chromosomes in the GnomAD database, including 477,870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.77 ( 45275 hom., cov: 29)

Exomes 𝑓: 0.77 ( 432595 hom. )

Consequence

C3
NM_000064.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -5.36

Publications

40 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=-0.94).

BP6

Variant 19-6697395-A-G is Benign according to our data. Variant chr19-6697395-A-G is described in ClinVar as Benign. ClinVar VariationId is 330300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.36 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.892 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4 link	c.2745T>C	p.Ala915Ala	synonymous_variant	Exon 21 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.2745T>C	p.Ala915Ala	synonymous_variant	Exon 21 of 41	1	NM_000064.4	ENSP00000245907.4		P01024

Frequencies

GnomAD3 genomes

AF:

0.772

AC:

117094

AN:

151768

Hom.:

45236

Cov.:

show subpopulations

Gnomad AFR

AF:

0.758

Gnomad AMI

AF:

0.610

Gnomad AMR

AF:

0.842

Gnomad ASJ

AF:

0.813

Gnomad EAS

AF:

0.914

Gnomad SAS

AF:

0.813

Gnomad FIN

AF:

0.758

Gnomad MID

AF:

0.766

Gnomad NFE

AF:

0.752

Gnomad OTH

AF:

0.800

GnomAD2 exomes

AF:

0.797

AC:

200347

AN:

251438

AF XY:

0.793

show subpopulations

Gnomad AFR exome

AF:

0.756

Gnomad AMR exome

AF:

0.893

Gnomad ASJ exome

AF:

0.797

Gnomad EAS exome

AF:

0.911

Gnomad FIN exome

AF:

0.758

Gnomad NFE exome

AF:

0.758

Gnomad OTH exome

AF:

0.803

GnomAD4 exome

AF:

0.768

AC:

1122592

AN:

1461712

Hom.:

432595

Cov.:

AF XY:

0.768

AC XY:

558550

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.761

AC:

25487

AN:

33470

American (AMR)

AF:

0.887

AC:

39678

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.795

AC:

20768

AN:

26136

East Asian (EAS)

AF:

0.929

AC:

36884

AN:

39700

South Asian (SAS)

AF:

0.807

AC:

69642

AN:

86252

European-Finnish (FIN)

AF:

0.754

AC:

40288

AN:

53414

Middle Eastern (MID)

AF:

0.800

AC:

4613

AN:

5768

European-Non Finnish (NFE)

AF:

0.754

AC:

838226

AN:

1111858

Other (OTH)

AF:

0.778

AC:

47006

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

15774

31548

47322

63096

78870

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20406

40812

61218

81624

102030

<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:

0.772

AC:

117188

AN:

151886

Hom.:

45275

Cov.:

AF XY:

0.775

AC XY:

57530

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.758

AC:

31381

AN:

41404

American (AMR)

AF:

0.843

AC:

12842

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.813

AC:

2820

AN:

3470

East Asian (EAS)

AF:

0.914

AC:

4719

AN:

5162

South Asian (SAS)

AF:

0.812

AC:

3892

AN:

4794

European-Finnish (FIN)

AF:

0.758

AC:

8001

AN:

10556

Middle Eastern (MID)

AF:

0.762

AC:

224

AN:

294

European-Non Finnish (NFE)

AF:

0.752

AC:

51077

AN:

67954

Other (OTH)

AF:

0.797

AC:

1681

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1324

2648

3971

5295

6619

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

864

1728

2592

3456

4320

<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:

0.765

Hom.:

221963

Bravo

AF:

0.780

Asia WGS

AF:

0.845

AC:

2938

AN:

3478

EpiCase

AF:

0.771

EpiControl

AF:

0.778

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

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

Jan 12, 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. -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 12, 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 12, 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

-0.94

CADD

Benign

0.068

(source)

DANN

Benign

0.25

PhyloP100

-5.4

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over