rs2287845

Variant names:

• chr19-6696586-G-A
• rs2287845
• NM_000064.4:c.2863+7C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-6696586-G-A
• chr19-6696586-G-C
• chr19-6696586-G-T

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.2863+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.639 in 1,612,156 control chromosomes in the GnomAD database, including 332,996 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33415 hom., cov: 30)
  • Exomes 𝑓: 0.64 (299581 hom.)
• Consequence: C3 NM_000064.4 splice_region, intron
• Scores: Splicing: ADA: 0.0005128
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.712
• Publications: 19 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 19-6696586-G-A is Benign according to our data. Variant chr19-6696586-G-A is described in ClinVar as Benign. ClinVar VariationId is 330297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.821 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.2863+7C>T		splice_region intron	N/A	NP_000055.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	ENST00000245907.11	TSL:1 MANE Select	c.2863+7C>T		splice_region intron	N/A	ENSP00000245907.4
	C3	ENST00000952696.1		c.2875+7C>T		splice_region intron	N/A	ENSP00000622755.1
	C3	ENST00000879543.1		c.2863+7C>T		splice_region intron	N/A	ENSP00000549602.1

Frequencies

GnomAD3 genomes AF: 0.660 AC: 100070 AN: 151660 Hom.: 33373 Cov.: 30

Gnomad AFR AF: 0.706

Gnomad AMI AF: 0.443

Gnomad AMR AF: 0.736

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.842

Gnomad SAS AF: 0.713

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.616

Gnomad OTH AF: 0.676

GnomAD2 exomes AF: 0.674 AC: 169368 AN: 251462 AF XY: 0.666

Gnomad AFR exome AF: 0.707

Gnomad AMR exome AF: 0.811

Gnomad ASJ exome AF: 0.597

Gnomad EAS exome AF: 0.838

Gnomad FIN exome AF: 0.566

Gnomad NFE exome AF: 0.618

Gnomad OTH exome AF: 0.664

GnomAD4 exome AF: 0.637 AC: 929802 AN: 1460380 Hom.: 299581 Cov.: 40 AF XY: 0.637 AC XY: 462804 AN XY: 726596

African (AFR) AF: 0.714 AC: 23873 AN: 33450

American (AMR) AF: 0.800 AC: 35791 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.593 AC: 15482 AN: 26126

East Asian (EAS) AF: 0.865 AC: 34331 AN: 39696

South Asian (SAS) AF: 0.706 AC: 60859 AN: 86236

European-Finnish (FIN) AF: 0.567 AC: 30261 AN: 53402

Middle Eastern (MID) AF: 0.673 AC: 3884 AN: 5768

European-Non Finnish (NFE) AF: 0.618 AC: 686205 AN: 1110624

Other (OTH) AF: 0.648 AC: 39116 AN: 60358

GnomAD4 genome AF: 0.660 AC: 100168 AN: 151776 Hom.: 33415 Cov.: 30 AF XY: 0.662 AC XY: 49098 AN XY: 74148

African (AFR) AF: 0.707 AC: 29237 AN: 41362

American (AMR) AF: 0.737 AC: 11226 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 2125 AN: 3466

East Asian (EAS) AF: 0.842 AC: 4349 AN: 5164

South Asian (SAS) AF: 0.711 AC: 3425 AN: 4814

European-Finnish (FIN) AF: 0.569 AC: 5967 AN: 10494

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.616 AC: 41822 AN: 67926

Other (OTH) AF: 0.673 AC: 1416 AN: 2104

Alfa AF: 0.636 Hom.: 45544

Bravo AF: 0.675

Asia WGS AF: 0.771 AC: 2680 AN: 3478

EpiCase AF: 0.634

EpiControl AF: 0.633

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Age related macular degeneration 9 (2)
-	-	2	Complement component 3 deficiency (2)
-	-	2	not specified (2)
-	-	1	Atypical hemolytic-uremic syndrome with C3 anomaly (1)
-	-	1	Atypical hemolytic-uremic syndrome;C3151071:Complement component 3 deficiency;C4055342:C3 glomerulonephritis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.51
DANN	Benign	0.41
PhyloP100		-0.71
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00051
dbscSNV1_RF	Benign	0.0
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: rs2287845; hg19: chr19-6696597; COSMIC: COSV55580011; COSMIC: COSV55580011;