19-6694990-G-C

Variant names:

• chr19-6694990-G-C
• rs10402876
• NM_000064.4:c.2951-356C>G

Variant summary

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

The NM_000064.4(C3):​c.2951-356C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 151,990 control chromosomes in the GnomAD database, including 18,829 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 0.48 (18829 hom., cov: 31)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00200
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.559 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	NM_000064.4	MANE Select	c.2951-356C>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.2951-356C>G		intron	N/A	ENSP00000245907.4	P01024
	C3	ENST00000952696.1		c.2963-356C>G		intron	N/A	ENSP00000622755.1
	C3	ENST00000879543.1		c.2948-356C>G		intron	N/A	ENSP00000549602.1

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73290 AN: 151870 Hom.: 18829 Cov.: 31

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.570

Gnomad ASJ AF: 0.669

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.487

Gnomad FIN AF: 0.536

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.556

Gnomad OTH AF: 0.538

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

GnomAD4 genome AF: 0.482 AC: 73310 AN: 151990 Hom.: 18829 Cov.: 31 AF XY: 0.483 AC XY: 35910 AN XY: 74292

African (AFR) AF: 0.297 AC: 12332 AN: 41456

American (AMR) AF: 0.569 AC: 8701 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.669 AC: 2323 AN: 3470

East Asian (EAS) AF: 0.475 AC: 2450 AN: 5162

South Asian (SAS) AF: 0.487 AC: 2339 AN: 4806

European-Finnish (FIN) AF: 0.536 AC: 5664 AN: 10560

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.556 AC: 37777 AN: 67938

Other (OTH) AF: 0.532 AC: 1126 AN: 2116

Alfa AF: 0.528 Hom.: 11247

Bravo AF: 0.478

Asia WGS AF: 0.457 AC: 1589 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.5
DANN	Benign	0.68
PhyloP100		0.0020
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: rs10402876; hg19: chr19-6695001;