rs344550

Variant names:

• chr19-6682942-C-G
• rs344550
• NM_000064.4:c.4173-713G>C

Variant summary

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

The NM_000064.4(C3):​c.4173-713G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.644 in 154,050 control chromosomes in the GnomAD database, including 32,037 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 0.64 (31693 hom., cov: 32)
  • Exomes 𝑓: 0.58 (344 hom.)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.457
• Publications: 18 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

ENSG00000297005 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4	c.4173-713G>C		intron_variant	Intron 33 of 40	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.4173-713G>C		intron_variant	Intron 33 of 40	1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.644 AC: 97948 AN: 151980 Hom.: 31672 Cov.: 32

Gnomad AFR AF: 0.645

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.638

Gnomad ASJ AF: 0.579

Gnomad EAS AF: 0.638

Gnomad SAS AF: 0.703

Gnomad FIN AF: 0.624

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.648

Gnomad OTH AF: 0.659

GnomAD4 exome AF: 0.581 AC: 1135 AN: 1952 Hom.: 344 Cov.: 0 AF XY: 0.574 AC XY: 561 AN XY: 978

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.555 AC: 234 AN: 422

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.567 AC: 17 AN: 30

South Asian (SAS) AF: 0.546 AC: 59 AN: 108

European-Finnish (FIN) AF: 0.417 AC: 5 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.598 AC: 783 AN: 1310

Other (OTH) AF: 0.529 AC: 37 AN: 70

GnomAD4 genome AF: 0.644 AC: 98019 AN: 152098 Hom.: 31693 Cov.: 32 AF XY: 0.643 AC XY: 47820 AN XY: 74346

African (AFR) AF: 0.645 AC: 26753 AN: 41462

American (AMR) AF: 0.638 AC: 9745 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 2006 AN: 3464

East Asian (EAS) AF: 0.636 AC: 3297 AN: 5182

South Asian (SAS) AF: 0.702 AC: 3389 AN: 4830

European-Finnish (FIN) AF: 0.624 AC: 6599 AN: 10580

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.648 AC: 44074 AN: 67992

Other (OTH) AF: 0.661 AC: 1394 AN: 2110

Alfa AF: 0.624 Hom.: 3683

Bravo AF: 0.645

Asia WGS AF: 0.672 AC: 2338 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.19
DANN	Benign	0.31
PhyloP100		-0.46
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: rs344550; hg19: chr19-6682953;