chr19-6686078-G-A

Variant names:

• chr19-6686078-G-A
• rs11569536
• NM_000064.4:c.3810+46C>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.3810+46C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0645 in 1,600,060 control chromosomes in the GnomAD database, including 3,721 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (291 hom., cov: 32)
  • Exomes 𝑓: 0.065 (3430 hom.)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0790
• Publications: 17 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=-0.88).
• BP6: Variant 19-6686078-G-A is Benign according to our data. Variant chr19-6686078-G-A is described in ClinVar as Benign. ClinVar VariationId is 1258093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0688 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	NM_000064.4	MANE Select	c.3810+46C>T		intron	N/A	NP_000055.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	ENST00000245907.11	TSL:1 MANE Select	c.3810+46C>T		intron	N/A	ENSP00000245907.4
	C3	ENST00000695654.1		c.2835+46C>T		intron	N/A	ENSP00000512085.1
	C3	ENST00000695653.1		c.1719+46C>T		intron	N/A	ENSP00000512084.1

Frequencies

GnomAD3 genomes AF: 0.0596 AC: 9073 AN: 152144 Hom.: 290 Cov.: 32

Gnomad AFR AF: 0.0635

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.0322

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.00904

Gnomad SAS AF: 0.0298

Gnomad FIN AF: 0.0575

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0705

Gnomad OTH AF: 0.0445

GnomAD2 exomes AF: 0.0489 AC: 12284 AN: 251374 AF XY: 0.0489

Gnomad AFR exome AF: 0.0644

Gnomad AMR exome AF: 0.0220

Gnomad ASJ exome AF: 0.0296

Gnomad EAS exome AF: 0.0106

Gnomad FIN exome AF: 0.0574

Gnomad NFE exome AF: 0.0661

Gnomad OTH exome AF: 0.0452

GnomAD4 exome AF: 0.0650 AC: 94108 AN: 1447798 Hom.: 3430 Cov.: 30 AF XY: 0.0640 AC XY: 46144 AN XY: 720898

African (AFR) AF: 0.0643 AC: 2132 AN: 33174

American (AMR) AF: 0.0232 AC: 1039 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0324 AC: 845 AN: 26042

East Asian (EAS) AF: 0.00770 AC: 305 AN: 39630

South Asian (SAS) AF: 0.0318 AC: 2733 AN: 85938

European-Finnish (FIN) AF: 0.0595 AC: 3177 AN: 53374

Middle Eastern (MID) AF: 0.0141 AC: 69 AN: 4878

European-Non Finnish (NFE) AF: 0.0728 AC: 80136 AN: 1100210

Other (OTH) AF: 0.0614 AC: 3672 AN: 59848

GnomAD4 genome AF: 0.0596 AC: 9079 AN: 152262 Hom.: 291 Cov.: 32 AF XY: 0.0583 AC XY: 4337 AN XY: 74446

African (AFR) AF: 0.0634 AC: 2635 AN: 41534

American (AMR) AF: 0.0321 AC: 492 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 104 AN: 3470

East Asian (EAS) AF: 0.00906 AC: 47 AN: 5188

South Asian (SAS) AF: 0.0299 AC: 144 AN: 4824

European-Finnish (FIN) AF: 0.0575 AC: 610 AN: 10608

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0705 AC: 4796 AN: 68018

Other (OTH) AF: 0.0441 AC: 93 AN: 2110

Alfa AF: 0.0619 Hom.: 661

Bravo AF: 0.0568

Asia WGS AF: 0.0200 AC: 70 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.6
DANN	Benign	0.51
PhyloP100		0.079
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: rs11569536; hg19: chr19-6686089; COSMIC: COSV55568398; COSMIC: COSV55568398;