19-6697818-G-C

Variant names:

• chr19-6697818-G-C
• rs366510
• NM_000064.4:c.2441-24C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_000064.4(C3):​c.2441-24C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000673 in 1,605,804 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000033 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.54
• Publications: 22 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: ClinGen, Labcorp Genetics (formerly Invitae)
• complement component 3 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet
• C3 glomerulonephritis

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000708 (103/1454236) while in subpopulation NFE AF = 0.000092 (102/1108944). AF 95% confidence interval is 0.0000771. There are 0 homozygotes in GnomAdExome4. There are 52 alleles in the male GnomAdExome4 subpopulation. Median coverage is 39. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	NM_000064.4	MANE Select	c.2441-24C>G		intron	N/A	NP_000055.2	P01024

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	ENST00000245907.11	TSL:1 MANE Select	c.2441-24C>G		intron	N/A	ENSP00000245907.4	P01024
	C3	ENST00000952696.1		c.2453-24C>G		intron	N/A	ENSP00000622755.1
	C3	ENST00000879543.1		c.2441-24C>G		intron	N/A	ENSP00000549602.1

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151568 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000250 AC: 6 AN: 239922 AF XY: 0.0000386

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000464

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.0000708 AC: 103 AN: 1454236 Hom.: 0 Cov.: 39 AF XY: 0.0000719 AC XY: 52 AN XY: 722884

African (AFR) AF: 0.00 AC: 0 AN: 33274

American (AMR) AF: 0.00 AC: 0 AN: 43674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39482

South Asian (SAS) AF: 0.00 AC: 0 AN: 85416

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4512

European-Non Finnish (NFE) AF: 0.0000920 AC: 102 AN: 1108944

Other (OTH) AF: 0.0000167 AC: 1 AN: 60050

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151568 Hom.: 0 Cov.: 28 AF XY: 0.0000405 AC XY: 3 AN XY: 74002

African (AFR) AF: 0.00 AC: 0 AN: 41194

American (AMR) AF: 0.00 AC: 0 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67902

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 42179

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.045
DANN	Benign	0.45
PhyloP100		-4.5
Mutation Taster		=100/0	polymorphism

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: rs366510; hg19: chr19-6697829;