rs1047286

Variant names:

• chr19-6713251-G-A
• rs1047286
• NM_000064.4:c.941C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-6713251-G-A
• chr19-6713251-G-C

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.941C>T​(p.Pro314Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,613,434 control chromosomes in the GnomAD database, including 29,494 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1874 hom., cov: 31)
  • Exomes 𝑓: 0.19 (27620 hom.)
• Consequence: C3 NM_000064.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.719
• Publications: 113 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.6191297E-4).
• BP6: Variant 19-6713251-G-A is Benign according to our data. Variant chr19-6713251-G-A is described in ClinVar as Benign. ClinVar VariationId is 17057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.2 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.941C>T	p.Pro314Leu	missense	Exon 9 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.941C>T	p.Pro314Leu	missense	Exon 9 of 41	ENSP00000245907.4	P01024
	C3	ENST00000952696.1		c.941C>T	p.Pro314Leu	missense	Exon 9 of 42	ENSP00000622755.1
	C3	ENST00000879543.1		c.941C>T	p.Pro314Leu	missense	Exon 9 of 41	ENSP00000549602.1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20348 AN: 151964 Hom.: 1874 Cov.: 31

Gnomad AFR AF: 0.0377

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0923

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.130

GnomAD2 exomes AF: 0.141 AC: 35480 AN: 250810 AF XY: 0.145

Gnomad AFR exome AF: 0.0340

Gnomad AMR exome AF: 0.0750

Gnomad ASJ exome AF: 0.212

Gnomad EAS exome AF: 0.000707

Gnomad FIN exome AF: 0.166

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.158

GnomAD4 exome AF: 0.185 AC: 270924 AN: 1461352 Hom.: 27620 Cov.: 35 AF XY: 0.183 AC XY: 133204 AN XY: 726968

African (AFR) AF: 0.0313 AC: 1047 AN: 33480

American (AMR) AF: 0.0767 AC: 3430 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 5647 AN: 26134

East Asian (EAS) AF: 0.000579 AC: 23 AN: 39700

South Asian (SAS) AF: 0.101 AC: 8677 AN: 86252

European-Finnish (FIN) AF: 0.172 AC: 9141 AN: 53000

Middle Eastern (MID) AF: 0.135 AC: 780 AN: 5768

European-Non Finnish (NFE) AF: 0.208 AC: 231454 AN: 1111920

Other (OTH) AF: 0.178 AC: 10725 AN: 60382

GnomAD4 genome AF: 0.134 AC: 20349 AN: 152082 Hom.: 1874 Cov.: 31 AF XY: 0.131 AC XY: 9733 AN XY: 74336

African (AFR) AF: 0.0376 AC: 1562 AN: 41528

American (AMR) AF: 0.102 AC: 1560 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 765 AN: 3464

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5178

South Asian (SAS) AF: 0.0935 AC: 451 AN: 4826

European-Finnish (FIN) AF: 0.172 AC: 1820 AN: 10554

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13803 AN: 67944

Other (OTH) AF: 0.129 AC: 272 AN: 2108

Alfa AF: 0.177 Hom.: 5805

Bravo AF: 0.124

ESP6500AA AF: 0.0402 AC: 177

ESP6500EA AF: 0.205 AC: 1760

ExAC AF: 0.143 AC: 17319

Asia WGS AF: 0.0490 AC: 171 AN: 3478

EpiCase AF: 0.199

EpiControl AF: 0.197

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Age related macular degeneration 9 (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 POLYMORPHISM, HAV 4-1 PLUS/MINUS TYPE (1)
-	-	1	Complement component 3 deficiency (1)
-	-	1	Focal segmental glomerulosclerosis (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Benign	0.79
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.00086	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.72
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.020
Sift	Uncertain	0.028	D
Sift4G	Benign	0.11	T
Polyphen		0.23	B
Vest4		0.022
MPC		0.60
ClinPred		0.0081	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.68
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1047286; hg19: chr19-6713262; COSMIC: COSV55573811; COSMIC: COSV55573811;