19-6709063-C-T

Variant names:

• chr19-6709063-C-T
• rs11569429
• NM_000064.4:c.1845+621G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000064.4(C3):​c.1845+621G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 152,174 control chromosomes in the GnomAD database, including 1,205 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (1205 hom., cov: 31)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.542
• Publications: 12 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.143 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	NM_000064.4	MANE Select	c.1845+621G>A		intron	N/A	NP_000055.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	ENST00000245907.11	TSL:1 MANE Select	c.1845+621G>A		intron	N/A	ENSP00000245907.4
	C3	ENST00000695654.1		c.969+621G>A		intron	N/A	ENSP00000512085.1
	C3	ENST00000695652.1		c.1722+621G>A		intron	N/A	ENSP00000512083.1

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17377 AN: 152056 Hom.: 1203 Cov.: 31

Gnomad AFR AF: 0.0463

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.0834

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.136

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.114 AC: 17387 AN: 152174 Hom.: 1205 Cov.: 31 AF XY: 0.115 AC XY: 8558 AN XY: 74382

African (AFR) AF: 0.0463 AC: 1922 AN: 41524

American (AMR) AF: 0.111 AC: 1694 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 567 AN: 3470

East Asian (EAS) AF: 0.116 AC: 602 AN: 5184

South Asian (SAS) AF: 0.0845 AC: 407 AN: 4816

European-Finnish (FIN) AF: 0.177 AC: 1880 AN: 10594

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.145 AC: 9855 AN: 67998

Other (OTH) AF: 0.135 AC: 285 AN: 2110

Alfa AF: 0.138 Hom.: 3014

Bravo AF: 0.108

Asia WGS AF: 0.0890 AC: 309 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.8
DANN	Benign	0.66
PhyloP100		0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11569429; hg19: chr19-6709074;