rs344555

Variant names:

• chr19-6679349-T-C
• rs344555
• NM_000064.4:c.4546+58A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000064.4(C3):​c.4546+58A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.776 in 1,484,326 control chromosomes in the GnomAD database, including 449,094 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (48732 hom., cov: 31)
  • Exomes 𝑓: 0.77 (400362 hom.)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.581
• Publications: 30 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-6679349-T-C is Benign according to our data. Variant chr19-6679349-T-C is described in ClinVar as Benign. ClinVar VariationId is 1192668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4	c.4546+58A>G		intron_variant	Intron 37 of 40	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.4546+58A>G		intron_variant	Intron 37 of 40	1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.797 AC: 121167 AN: 151956 Hom.: 48680 Cov.: 31

Gnomad AFR AF: 0.891

Gnomad AMI AF: 0.724

Gnomad AMR AF: 0.744

Gnomad ASJ AF: 0.681

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.829

Gnomad FIN AF: 0.725

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.776

Gnomad OTH AF: 0.798

GnomAD4 exome AF: 0.774 AC: 1030735 AN: 1332252 Hom.: 400362 Cov.: 20 AF XY: 0.776 AC XY: 519644 AN XY: 669914

African (AFR) AF: 0.899 AC: 27734 AN: 30866

American (AMR) AF: 0.702 AC: 31289 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 17275 AN: 25292

East Asian (EAS) AF: 0.668 AC: 26066 AN: 39032

South Asian (SAS) AF: 0.831 AC: 69551 AN: 83732

European-Finnish (FIN) AF: 0.749 AC: 39944 AN: 53328

Middle Eastern (MID) AF: 0.810 AC: 4504 AN: 5558

European-Non Finnish (NFE) AF: 0.776 AC: 771164 AN: 993828

Other (OTH) AF: 0.771 AC: 43208 AN: 56052

GnomAD4 genome AF: 0.797 AC: 121276 AN: 152074 Hom.: 48732 Cov.: 31 AF XY: 0.792 AC XY: 58888 AN XY: 74324

African (AFR) AF: 0.891 AC: 36970 AN: 41504

American (AMR) AF: 0.743 AC: 11352 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.681 AC: 2362 AN: 3470

East Asian (EAS) AF: 0.702 AC: 3615 AN: 5152

South Asian (SAS) AF: 0.828 AC: 3995 AN: 4822

European-Finnish (FIN) AF: 0.725 AC: 7672 AN: 10578

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.776 AC: 52744 AN: 67968

Other (OTH) AF: 0.799 AC: 1682 AN: 2104

Alfa AF: 0.777 Hom.: 52312

Bravo AF: 0.800

Asia WGS AF: 0.775 AC: 2697 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Age related macular degeneration 9 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Complement component 3 deficiency Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.062
DANN	Benign	0.44
PhyloP100		-0.58
PromoterAI		0.011	Neutral
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: rs344555; hg19: chr19-6679360;