19-6709693-C-T

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.1836G>A(p.Thr612Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,612,072 control chromosomes in the GnomAD database, including 19,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 1934 hom., cov: 28)

Exomes 𝑓: 0.14 ( 17604 hom. )

Consequence

C3
NM_000064.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.27

Publications

50 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=-0.67).

BP6

Variant 19-6709693-C-T is Benign according to our data. Variant chr19-6709693-C-T is described in ClinVar as Benign. ClinVar VariationId is 330317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.27 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000064.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	NM_000064.4	MANE Select	c.1836G>A	p.Thr612Thr	synonymous	Exon 14 of 41	NP_000055.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
C3	ENST00000245907.11	TSL:1 MANE Select	c.1836G>A	p.Thr612Thr	synonymous	Exon 14 of 41	ENSP00000245907.4
C3	ENST00000952696.1		c.1836G>A	p.Thr612Thr	synonymous	Exon 14 of 42	ENSP00000622755.1
C3	ENST00000879543.1		c.1836G>A	p.Thr612Thr	synonymous	Exon 14 of 41	ENSP00000549602.1

Frequencies

GnomAD3 genomes

AF:

0.147

AC:

22262

AN:

151292

Hom.:

1932

Cov.:

show subpopulations

Gnomad AFR

AF:

0.120

Gnomad AMI

AF:

0.191

Gnomad AMR

AF:

0.126

Gnomad ASJ

AF:

0.194

Gnomad EAS

AF:

0.435

Gnomad SAS

AF:

0.260

Gnomad FIN

AF:

0.192

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.129

Gnomad OTH

AF:

0.132

GnomAD2 exomes

AF:

0.172

AC:

43146

AN:

251408

AF XY:

0.175

show subpopulations

Gnomad AFR exome

AF:

0.118

Gnomad AMR exome

AF:

0.115

Gnomad ASJ exome

AF:

0.196

Gnomad EAS exome

AF:

0.432

Gnomad FIN exome

AF:

0.193

Gnomad NFE exome

AF:

0.132

Gnomad OTH exome

AF:

0.166

GnomAD4 exome

AF:

0.145

AC:

211286

AN:

1460662

Hom.:

17604

Cov.:

AF XY:

0.147

AC XY:

107013

AN XY:

726650

show subpopulations

African (AFR)

AF:

0.122

AC:

4075

AN:

33462

American (AMR)

AF:

0.114

AC:

5100

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.200

AC:

5211

AN:

26106

East Asian (EAS)

AF:

0.417

AC:

16550

AN:

39646

South Asian (SAS)

AF:

0.225

AC:

19372

AN:

86252

European-Finnish (FIN)

AF:

0.197

AC:

10466

AN:

53010

Middle Eastern (MID)

AF:

0.132

AC:

761

AN:

5764

European-Non Finnish (NFE)

AF:

0.126

AC:

140245

AN:

1111398

Other (OTH)

AF:

0.158

AC:

9506

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

9940

19881

29821

39762

49702

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5286

10572

15858

21144

26430

<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:

0.147

AC:

22278

AN:

151410

Hom.:

1934

Cov.:

AF XY:

0.153

AC XY:

11333

AN XY:

73902

show subpopulations

African (AFR)

AF:

0.121

AC:

4983

AN:

41268

American (AMR)

AF:

0.125

AC:

1902

AN:

15168

Ashkenazi Jewish (ASJ)

AF:

0.194

AC:

671

AN:

3464

East Asian (EAS)

AF:

0.435

AC:

2220

AN:

5098

South Asian (SAS)

AF:

0.260

AC:

1242

AN:

4782

European-Finnish (FIN)

AF:

0.192

AC:

1999

AN:

10422

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.129

AC:

8782

AN:

67906

Other (OTH)

AF:

0.129

AC:

271

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

921

1842

2762

3683

4604

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

252

504

756

1008

1260

<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:

0.138

Hom.:

5300

Bravo

AF:

0.140

Asia WGS

AF:

0.303

AC:

1051

AN:

3478

EpiCase

AF:

0.128

EpiControl

AF:

0.125

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Age related macular degeneration 9 (2)

Complement component 3 deficiency (2)

Atypical hemolytic-uremic syndrome with C3 anomaly (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

3.4

(source)

DANN

Benign

0.74

PhyloP100

-1.3

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over