Genetic Variant C3:c.3646+98A>G (chr19-6686648-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000064.4(C3):c.3646+98A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 1,299,660 control chromosomes in the GnomAD database, including 494,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.87 ( 58228 hom., cov: 31)

Exomes 𝑓: 0.87 ( 436220 hom. )

Consequence

C3
NM_000064.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.280

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 19-6686648-T-C is Benign according to our data. Variant chr19-6686648-T-C is described in ClinVar as [Benign]. Clinvar id is 1192670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.965 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4 link	c.3646+98A>G		intron_variant	Intron 28 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.3646+98A>G		intron_variant	Intron 28 of 40	1	NM_000064.4	ENSP00000245907.4		P01024

Frequencies

GnomAD3 genomes

AF:

0.874

AC:

132945

AN:

152058

Hom.:

58196

Cov.:

show subpopulations

Gnomad AFR

AF:

0.886

Gnomad AMI

AF:

0.889

Gnomad AMR

AF:

0.894

Gnomad ASJ

AF:

0.872

Gnomad EAS

AF:

0.988

Gnomad SAS

AF:

0.863

Gnomad FIN

AF:

0.859

Gnomad MID

AF:

0.820

Gnomad NFE

AF:

0.857

Gnomad OTH

AF:

0.877

GnomAD4 exome

AF:

0.871

AC:

999587

AN:

1147484

Hom.:

436220

Cov.:

AF XY:

0.869

AC XY:

509024

AN XY:

585520

show subpopulations

Gnomad4 AFR exome

AF:

0.888

Gnomad4 AMR exome

AF:

0.931

Gnomad4 ASJ exome

AF:

0.854

Gnomad4 EAS exome

AF:

0.984

Gnomad4 SAS exome

AF:

0.860

Gnomad4 FIN exome

AF:

0.858

Gnomad4 NFE exome

AF:

0.864

Gnomad4 OTH exome

AF:

0.876

GnomAD4 genome

AF:

0.874

AC:

133031

AN:

152176

Hom.:

58228

Cov.:

AF XY:

0.875

AC XY:

65074

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.886

Gnomad4 AMR

AF:

0.894

Gnomad4 ASJ

AF:

0.872

Gnomad4 EAS

AF:

0.988

Gnomad4 SAS

AF:

0.861

Gnomad4 FIN

AF:

0.859

Gnomad4 NFE

AF:

0.857

Gnomad4 OTH

AF:

0.874

Alfa

AF:

0.861

Hom.:

37348

Bravo

AF:

0.881

Asia WGS

AF:

0.907

AC:

3154

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Age related macular degeneration 9

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Complement component 3 deficiency

Benign:1

Jul 14, 2021

Genome-Nilou Lab

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

-0.89

CADD

Benign

6.7

DANN

Benign

0.75

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over