NM_000064.4:c.2745T>C

Variant names:

• chr19-6697395-A-G
• rs423490
• NM_000064.4:c.2745T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000064.4(C3):​c.2745T>C​(p.Ala915Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.768 in 1,613,598 control chromosomes in the GnomAD database, including 477,870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45275 hom., cov: 29)
  • Exomes 𝑓: 0.77 (432595 hom.)
• Consequence: C3 NM_000064.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -5.36
• Publications: 40 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: ClinGen, Labcorp Genetics (formerly Invitae)
• complement component 3 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet
• C3 glomerulonephritis

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 19-6697395-A-G is Benign according to our data. Variant chr19-6697395-A-G is described in ClinVar as Benign. ClinVar VariationId is 330300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.892 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.2745T>C	p.Ala915Ala	synonymous	Exon 21 of 41	NP_000055.2	P01024

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	ENST00000245907.11	TSL:1 MANE Select	c.2745T>C	p.Ala915Ala	synonymous	Exon 21 of 41	ENSP00000245907.4	P01024
	C3	ENST00000952696.1		c.2757T>C	p.Ala919Ala	synonymous	Exon 22 of 42	ENSP00000622755.1
	C3	ENST00000879543.1		c.2745T>C	p.Ala915Ala	synonymous	Exon 21 of 41	ENSP00000549602.1

Frequencies

GnomAD3 genomes AF: 0.772 AC: 117094 AN: 151768 Hom.: 45236 Cov.: 29

Gnomad AFR AF: 0.758

Gnomad AMI AF: 0.610

Gnomad AMR AF: 0.842

Gnomad ASJ AF: 0.813

Gnomad EAS AF: 0.914

Gnomad SAS AF: 0.813

Gnomad FIN AF: 0.758

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.752

Gnomad OTH AF: 0.800

GnomAD2 exomes AF: 0.797 AC: 200347 AN: 251438 AF XY: 0.793

Gnomad AFR exome AF: 0.756

Gnomad AMR exome AF: 0.893

Gnomad ASJ exome AF: 0.797

Gnomad EAS exome AF: 0.911

Gnomad FIN exome AF: 0.758

Gnomad NFE exome AF: 0.758

Gnomad OTH exome AF: 0.803

GnomAD4 exome AF: 0.768 AC: 1122592 AN: 1461712 Hom.: 432595 Cov.: 55 AF XY: 0.768 AC XY: 558550 AN XY: 727166

African (AFR) AF: 0.761 AC: 25487 AN: 33470

American (AMR) AF: 0.887 AC: 39678 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.795 AC: 20768 AN: 26136

East Asian (EAS) AF: 0.929 AC: 36884 AN: 39700

South Asian (SAS) AF: 0.807 AC: 69642 AN: 86252

European-Finnish (FIN) AF: 0.754 AC: 40288 AN: 53414

Middle Eastern (MID) AF: 0.800 AC: 4613 AN: 5768

European-Non Finnish (NFE) AF: 0.754 AC: 838226 AN: 1111858

Other (OTH) AF: 0.778 AC: 47006 AN: 60390

GnomAD4 genome AF: 0.772 AC: 117188 AN: 151886 Hom.: 45275 Cov.: 29 AF XY: 0.775 AC XY: 57530 AN XY: 74240

African (AFR) AF: 0.758 AC: 31381 AN: 41404

American (AMR) AF: 0.843 AC: 12842 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.813 AC: 2820 AN: 3470

East Asian (EAS) AF: 0.914 AC: 4719 AN: 5162

South Asian (SAS) AF: 0.812 AC: 3892 AN: 4794

European-Finnish (FIN) AF: 0.758 AC: 8001 AN: 10556

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

European-Non Finnish (NFE) AF: 0.752 AC: 51077 AN: 67954

Other (OTH) AF: 0.797 AC: 1681 AN: 2108

Alfa AF: 0.765 Hom.: 221963

Bravo AF: 0.780

Asia WGS AF: 0.845 AC: 2938 AN: 3478

EpiCase AF: 0.771

EpiControl AF: 0.778

ClinVar

ClinVar submissions

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	-0.94
CADD	Benign	0.068
DANN	Benign	0.25
PhyloP100		-5.4
Mutation Taster		=99/1	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: rs423490; hg19: chr19-6697406; COSMIC: COSV55580035; COSMIC: COSV55580035;