19-6705235-T-C

Variant names:

• chr19-6705235-T-C
• rs11672613
• NM_000064.4:c.2245+1841A>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.2245+1841A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 152,054 control chromosomes in the GnomAD database, including 10,769 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 0.36 (10769 hom., cov: 32)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.288
• Publications: 27 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4	c.2245+1841A>G		intron_variant	Intron 17 of 40	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.2245+1841A>G		intron_variant	Intron 17 of 40	1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55134 AN: 151936 Hom.: 10770 Cov.: 32

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.479

Gnomad EAS AF: 0.414

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.407

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

GnomAD4 genome AF: 0.363 AC: 55148 AN: 152054 Hom.: 10769 Cov.: 32 AF XY: 0.366 AC XY: 27188 AN XY: 74310

African (AFR) AF: 0.204 AC: 8471 AN: 41510

American (AMR) AF: 0.485 AC: 7399 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 1661 AN: 3466

East Asian (EAS) AF: 0.415 AC: 2149 AN: 5176

South Asian (SAS) AF: 0.381 AC: 1838 AN: 4824

European-Finnish (FIN) AF: 0.393 AC: 4139 AN: 10544

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.415 AC: 28233 AN: 67958

Other (OTH) AF: 0.401 AC: 846 AN: 2110

Alfa AF: 0.405 Hom.: 44110

Bravo AF: 0.364

Asia WGS AF: 0.387 AC: 1345 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.7
DANN	Benign	0.83
PhyloP100		0.29
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: rs11672613; hg19: chr19-6705246;