rs3745568

Positions:

• chr19-6690602-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000245907.11(C3):​c.3489+27A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,575,370 control chromosomes in the GnomAD database, including 9,180 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (616 hom., cov: 33)
  • Exomes 𝑓: 0.11 (8564 hom.)
• Consequence: C3 ENST00000245907.11 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.93

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-6690602-T-G is Benign according to our data. Variant chr19-6690602-T-G is described in ClinVar as [Benign]. Clinvar id is 1223254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C3	NM_000064.4	c.3489+27A>C		intron_variant		ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.3489+27A>C		intron_variant		1	NM_000064.4	ENSP00000245907	P1

Frequencies

GnomAD3 genomes AF: 0.0793 AC: 12062 AN: 152182 Hom.: 616 Cov.: 33

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.0553

Gnomad ASJ AF: 0.0672

Gnomad EAS AF: 0.0792

Gnomad SAS AF: 0.0816

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.0693

GnomAD3 exomes AF: 0.0886 AC: 22259 AN: 251286 Hom.: 1122 AF XY: 0.0912 AC XY: 12384 AN XY: 135816

Gnomad AFR exome AF: 0.0185

Gnomad AMR exome AF: 0.0465

Gnomad ASJ exome AF: 0.0682

Gnomad EAS exome AF: 0.0813

Gnomad SAS exome AF: 0.0833

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.0874

GnomAD4 exome AF: 0.106 AC: 150937 AN: 1423070 Hom.: 8564 Cov.: 27 AF XY: 0.106 AC XY: 75220 AN XY: 710166

Gnomad4 AFR exome AF: 0.0172

Gnomad4 AMR exome AF: 0.0482

Gnomad4 ASJ exome AF: 0.0736

Gnomad4 EAS exome AF: 0.0632

Gnomad4 SAS exome AF: 0.0819

Gnomad4 FIN exome AF: 0.111

Gnomad4 NFE exome AF: 0.116

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.0792 AC: 12056 AN: 152300 Hom.: 616 Cov.: 33 AF XY: 0.0786 AC XY: 5852 AN XY: 74456

Gnomad4 AFR AF: 0.0199

Gnomad4 AMR AF: 0.0554

Gnomad4 ASJ AF: 0.0672

Gnomad4 EAS AF: 0.0788

Gnomad4 SAS AF: 0.0808

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.0705

Alfa AF: 0.104 Hom.: 827

Bravo AF: 0.0728

Asia WGS AF: 0.0800 AC: 279 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.10
DANN	Benign	0.67
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

Other links and lift over

dbSNP: rs3745568; hg19: chr19-6690613;