rs147859257

Variant names:

• chr19-6718135-T-G
• rs147859257
• NM_000064.4:c.463A>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000064.4(C3):​c.463A>C​(p.Lys155Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00379 in 1,614,084 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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 0.0024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (18 hom.)
• Consequence: C3 NM_000064.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6 O:1
• Conservation: PhyloP100: -0.762
• Publications: 70 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 -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000064.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.010331094).
• BP6: Variant 19-6718135-T-G is Benign according to our data. Variant chr19-6718135-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 92162.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00239 (364/152206) while in subpopulation NFE AF = 0.00446 (303/67988). AF 95% confidence interval is 0.00404. There are 0 homozygotes in GnomAd4. There are 156 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 18 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	NM_000064.4	MANE Select	c.463A>C	p.Lys155Gln	missense	Exon 4 of 41	NP_000055.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	ENST00000245907.11	TSL:1 MANE Select	c.463A>C	p.Lys155Gln	missense	Exon 4 of 41	ENSP00000245907.4
	C3	ENST00000952696.1		c.463A>C	p.Lys155Gln	missense	Exon 4 of 42	ENSP00000622755.1
	C3	ENST00000879543.1		c.463A>C	p.Lys155Gln	missense	Exon 4 of 41	ENSP00000549602.1

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 364 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00446

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00279 AC: 702 AN: 251454 AF XY: 0.00274

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00564

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00394 AC: 5761 AN: 1461878 Hom.: 18 Cov.: 34 AF XY: 0.00381 AC XY: 2772 AN XY: 727236

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.000581 AC: 26 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000765 AC: 20 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00127 AC: 68 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00492 AC: 5473 AN: 1112006

Other (OTH) AF: 0.00262 AC: 158 AN: 60396

GnomAD4 genome AF: 0.00239 AC: 364 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.00210 AC XY: 156 AN XY: 74414

African (AFR) AF: 0.000506 AC: 21 AN: 41526

American (AMR) AF: 0.000850 AC: 13 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000943 AC: 10 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00446 AC: 303 AN: 67988

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00446 Hom.: 5

Bravo AF: 0.00230

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00336 AC: 408

EpiCase AF: 0.00305

EpiControl AF: 0.00326

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (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 with C3 anomaly (1)
-	-	1	Atypical hemolytic-uremic syndrome;C3151071:Complement component 3 deficiency;C4055342:C3 glomerulonephritis (1)
-	-	1	C3-related disorder (1)
-	-	1	Complement component 3 deficiency (1)
-	1	-	not specified (1)
-	1	-	Retinal dystrophy (1)
-	-	-	MACULAR DEGENERATION, AGE-RELATED, 9, SUSCEPTIBILITY TO (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	11
DANN	Benign	0.82
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-0.76
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.067
Sift	Benign	0.47	T
Sift4G	Benign	0.55	T
Polyphen		0.12	B
Vest4		0.14
MVP		0.79
MPC		0.64
ClinPred		0.014	T
GERP RS		1.3
Varity_R		0.59
gMVP		0.75
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		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: rs147859257; hg19: chr19-6718146; COSMIC: COSV55572996; COSMIC: COSV55572996;