chr19-6706030-G-A

Variant names:

• chr19-6706030-G-A
• rs8107911
• NM_000064.4:c.2245+1046C>T

Variant summary

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

The NM_000064.4(C3):​c.2245+1046C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.813 in 152,240 control chromosomes in the GnomAD database, including 50,668 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 0.81 (50668 hom., cov: 33)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.357
• Publications: 7 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.894 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.2245+1046C>T		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.2245+1046C>T		intron	N/A	ENSP00000245907.4
	C3	ENST00000695654.1		c.1369+1046C>T		intron	N/A	ENSP00000512085.1
	C3	ENST00000695652.1		c.2122+1046C>T		intron	N/A	ENSP00000512083.1

Frequencies

GnomAD3 genomes AF: 0.813 AC: 123737 AN: 152122 Hom.: 50628 Cov.: 33

Gnomad AFR AF: 0.902

Gnomad AMI AF: 0.610

Gnomad AMR AF: 0.858

Gnomad ASJ AF: 0.827

Gnomad EAS AF: 0.913

Gnomad SAS AF: 0.813

Gnomad FIN AF: 0.758

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.752

Gnomad OTH AF: 0.826

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

GnomAD4 genome AF: 0.813 AC: 123834 AN: 152240 Hom.: 50668 Cov.: 33 AF XY: 0.815 AC XY: 60674 AN XY: 74426

African (AFR) AF: 0.902 AC: 37474 AN: 41552

American (AMR) AF: 0.858 AC: 13117 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.827 AC: 2871 AN: 3472

East Asian (EAS) AF: 0.914 AC: 4743 AN: 5192

South Asian (SAS) AF: 0.811 AC: 3915 AN: 4828

European-Finnish (FIN) AF: 0.758 AC: 8021 AN: 10582

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.752 AC: 51170 AN: 68006

Other (OTH) AF: 0.823 AC: 1742 AN: 2116

Alfa AF: 0.767 Hom.: 14278

Bravo AF: 0.828

Asia WGS AF: 0.849 AC: 2952 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.54
DANN	Benign	0.50
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8107911; hg19: chr19-6706041;