rs3745568

Variant names:

• chr19-6690602-T-G
• rs3745568
• NM_000064.4:c.3489+27A>C

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.3489+27A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,575,370 control chromosomes in the GnomAD database, including 9,180 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (616 hom., cov: 33)
  • Exomes 𝑓: 0.11 (8564 hom.)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.93
• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-6690602-T-G is Benign according to our data. Variant chr19-6690602-T-G is described in ClinVar as Benign. ClinVar VariationId is 1223254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4	c.3489+27A>C		intron_variant	Intron 27 of 40	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.3489+27A>C		intron_variant	Intron 27 of 40	1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.0793 AC: 12062 AN: 152182 Hom.: 616 Cov.: 33

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.0553

Gnomad ASJ AF: 0.0672

Gnomad EAS AF: 0.0792

Gnomad SAS AF: 0.0816

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.0693

GnomAD2 exomes AF: 0.0886 AC: 22259 AN: 251286 AF XY: 0.0912

Gnomad AFR exome AF: 0.0185

Gnomad AMR exome AF: 0.0465

Gnomad ASJ exome AF: 0.0682

Gnomad EAS exome AF: 0.0813

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.0874

GnomAD4 exome AF: 0.106 AC: 150937 AN: 1423070 Hom.: 8564 Cov.: 27 AF XY: 0.106 AC XY: 75220 AN XY: 710166

African (AFR) AF: 0.0172 AC: 564 AN: 32734

American (AMR) AF: 0.0482 AC: 2153 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.0736 AC: 1905 AN: 25896

East Asian (EAS) AF: 0.0632 AC: 2498 AN: 39520

South Asian (SAS) AF: 0.0819 AC: 7005 AN: 85494

European-Finnish (FIN) AF: 0.111 AC: 5900 AN: 53388

Middle Eastern (MID) AF: 0.0722 AC: 411 AN: 5694

European-Non Finnish (NFE) AF: 0.116 AC: 124462 AN: 1076464

Other (OTH) AF: 0.102 AC: 6039 AN: 59202

GnomAD4 genome AF: 0.0792 AC: 12056 AN: 152300 Hom.: 616 Cov.: 33 AF XY: 0.0786 AC XY: 5852 AN XY: 74456

African (AFR) AF: 0.0199 AC: 826 AN: 41560

American (AMR) AF: 0.0554 AC: 847 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0672 AC: 233 AN: 3466

East Asian (EAS) AF: 0.0788 AC: 409 AN: 5188

South Asian (SAS) AF: 0.0808 AC: 390 AN: 4826

European-Finnish (FIN) AF: 0.109 AC: 1155 AN: 10606

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7758 AN: 68034

Other (OTH) AF: 0.0705 AC: 149 AN: 2114

Alfa AF: 0.104 Hom.: 877

Bravo AF: 0.0728

Asia WGS AF: 0.0800 AC: 279 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2021

GeneDx

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	0.10
DANN	Benign	0.67
PhyloP100		-1.9
PromoterAI		0.0031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs3745568; hg19: chr19-6690613; COSMIC: COSV107198656; COSMIC: COSV107198656;