NM_000064.4:c.4855A>C

Variant names:

• chr19-6678019-T-G
• rs2230210
• NM_000064.4:c.4855A>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000064.4(C3):​c.4855A>C​(p.Ser1619Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,613,968 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (3 hom.)
• Consequence: C3 NM_000064.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:9
• Conservation: PhyloP100: 0.709
• Publications: 16 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06986827).
• BP6: Variant 19-6678019-T-G is Benign according to our data. Variant chr19-6678019-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 330271.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00136 (207/152078) while in subpopulation NFE AF = 0.00252 (171/67980). AF 95% confidence interval is 0.00221. There are 1 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

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.4855A>C	p.Ser1619Arg	missense	Exon 41 of 41	NP_000055.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	ENST00000245907.11	TSL:1 MANE Select	c.4855A>C	p.Ser1619Arg	missense	Exon 41 of 41	ENSP00000245907.4
	C3	ENST00000952696.1		c.4867A>C	p.Ser1623Arg	missense	Exon 42 of 42	ENSP00000622755.1
	C3	ENST00000879543.1		c.4852A>C	p.Ser1618Arg	missense	Exon 41 of 41	ENSP00000549602.1

Frequencies

GnomAD3 genomes AF: 0.00136 AC: 207 AN: 151960 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000984

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00252

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.00118 AC: 298 AN: 251478 AF XY: 0.00116

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00222

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00199 AC: 2916 AN: 1461890 Hom.: 3 Cov.: 35 AF XY: 0.00192 AC XY: 1399 AN XY: 727244

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.000760 AC: 34 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00250 AC: 2783 AN: 1112010

Other (OTH) AF: 0.00113 AC: 68 AN: 60396

GnomAD4 genome AF: 0.00136 AC: 207 AN: 152078 Hom.: 1 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74336

African (AFR) AF: 0.000361 AC: 15 AN: 41502

American (AMR) AF: 0.000983 AC: 15 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00252 AC: 171 AN: 67980

Other (OTH) AF: 0.000475 AC: 1 AN: 2104

Alfa AF: 0.00221 Hom.: 3

Bravo AF: 0.00149

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00110 AC: 133

EpiCase AF: 0.00202

EpiControl AF: 0.00219

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	2	-	Complement component 3 deficiency (2)
-	-	2	not specified (2)
-	-	1	Age related macular degeneration 9 (1)
-	1	-	Age related macular degeneration 9;C2752037:Atypical hemolytic-uremic syndrome with C3 anomaly;C3151071:Complement component 3 deficiency (1)
-	-	1	Atypical hemolytic-uremic syndrome (1)
-	-	1	Atypical hemolytic-uremic syndrome with C3 anomaly (1)
-	1	-	C3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.71
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.051
Sift	Benign	0.097	T
Sift4G	Benign	0.15	T
Polyphen		0.83	P
Vest4		0.67
MutPred		0.35		Loss of methylation at K1615 (P = 0.0641)
MVP		0.57
MPC		0.74
ClinPred		0.020	T
GERP RS		4.0
Varity_R		0.45
gMVP		0.83
Mutation Taster		=72/28	polymorphism

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: rs2230210; hg19: chr19-6678030;