19-6690760-C-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.3391-33G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,539,970 control chromosomes in the GnomAD database, including 11,704 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.11 ( 1027 hom., cov: 33)

Exomes 𝑓: 0.12 ( 10677 hom. )

Consequence

C3
NM_000064.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.429

Publications

17 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

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 19-6690760-C-T is Benign according to our data. Variant chr19-6690760-C-T is described in ClinVar as Benign. ClinVar VariationId is 1226583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4 link	c.3391-33G>A		intron_variant	Intron 26 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.3391-33G>A		intron_variant	Intron 26 of 40	1	NM_000064.4	ENSP00000245907.4		P01024

Frequencies

GnomAD3 genomes

AF:

0.106

AC:

16075

AN:

152190

Hom.:

1026

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0559

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.100

Gnomad ASJ

AF:

0.182

Gnomad EAS

AF:

0.0761

Gnomad SAS

AF:

0.0788

Gnomad FIN

AF:

0.177

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.126

Gnomad OTH

AF:

0.119

GnomAD2 exomes

AF:

0.112

AC:

27336

AN:

244086

AF XY:

0.114

show subpopulations

Gnomad AFR exome

AF:

0.0537

Gnomad AMR exome

AF:

0.0749

Gnomad ASJ exome

AF:

0.180

Gnomad EAS exome

AF:

0.0762

Gnomad FIN exome

AF:

0.180

Gnomad NFE exome

AF:

0.126

Gnomad OTH exome

AF:

0.126

GnomAD4 exome

AF:

0.121

AC:

167383

AN:

1387660

Hom.:

10677

Cov.:

AF XY:

0.120

AC XY:

83259

AN XY:

694008

show subpopulations

African (AFR)

AF:

0.0519

AC:

1659

AN:

31992

American (AMR)

AF:

0.0799

AC:

3527

AN:

44130

Ashkenazi Jewish (ASJ)

AF:

0.179

AC:

4598

AN:

25672

East Asian (EAS)

AF:

0.0706

AC:

2773

AN:

39302

South Asian (SAS)

AF:

0.0801

AC:

6758

AN:

84404

European-Finnish (FIN)

AF:

0.177

AC:

9425

AN:

53122

Middle Eastern (MID)

AF:

0.0946

AC:

525

AN:

5548

European-Non Finnish (NFE)

AF:

0.126

AC:

131285

AN:

1045582

Other (OTH)

AF:

0.118

AC:

6833

AN:

57908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

6225

12450

18675

24900

31125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4650

9300

13950

18600

23250

<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:

0.106

AC:

16085

AN:

152310

Hom.:

1027

Cov.:

AF XY:

0.106

AC XY:

7928

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0559

AC:

2323

AN:

41564

American (AMR)

AF:

0.0999

AC:

1528

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.182

AC:

631

AN:

3472

East Asian (EAS)

AF:

0.0757

AC:

393

AN:

5194

South Asian (SAS)

AF:

0.0795

AC:

384

AN:

4832

European-Finnish (FIN)

AF:

0.177

AC:

1874

AN:

10608

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.126

AC:

8540

AN:

68020

Other (OTH)

AF:

0.120

AC:

253

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

727

1454

2181

2908

3635

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

360

540

720

900

<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:

0.115

Hom.:

2855

Bravo

AF:

0.0991

Asia WGS

AF:

0.0800

AC:

279

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 18, 2021

GeneDx

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

-0.68

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

0.43

BranchPoint Hunter

1.0

PromoterAI

-0.029

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

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