rs1047286

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

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. 14/20 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.719

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), C3. . Gene score misZ 2.7489 (greater than the threshold 3.09). Trascript score misZ 4.431 (greater than threshold 3.09). GenCC has associacion of gene with complement component 3 deficiency, C3 glomerulonephritis, atypical hemolytic-uremic syndrome with C3 anomaly.

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 id is 17057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6713251-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C3	NM_000064.4 linkuse as main transcript	c.941C>T	p.Pro314Leu	missense_variant	9/41	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11 linkuse as main transcript	c.941C>T	p.Pro314Leu	missense_variant	9/41	1	NM_000064.4	ENSP00000245907	P1

Frequencies

GnomAD3 genomes

AF:

0.134

AC:

20348

AN:

151964

Hom.:

1874

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.141

AC:

35480

AN:

250810

Hom.:

3166

AF XY:

0.145

AC XY:

19674

AN XY:

135634

show subpopulations

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 SAS exome

AF:

0.0989

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.:

AF XY:

0.183

AC XY:

133204

AN XY:

726968

show subpopulations

Gnomad4 AFR exome

AF:

0.0313

Gnomad4 AMR exome

AF:

0.0767

Gnomad4 ASJ exome

AF:

0.216

Gnomad4 EAS exome

AF:

0.000579

Gnomad4 SAS exome

AF:

0.101

Gnomad4 FIN exome

AF:

0.172

Gnomad4 NFE exome

AF:

0.208

Gnomad4 OTH exome

AF:

0.178

GnomAD4 genome

AF:

0.134

AC:

20349

AN:

152082

Hom.:

1874

Cov.:

AF XY:

0.131

AC XY:

9733

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0376

Gnomad4 AMR

AF:

0.102

Gnomad4 ASJ

AF:

0.221

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.0935

Gnomad4 FIN

AF:

0.172

Gnomad4 NFE

AF:

0.203

Gnomad4 OTH

AF:

0.129

Alfa

AF:

0.181

Hom.:

3719

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

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 30131807, 19168221, 24736606, 24036950, 21784901, 25688879) -

C3 POLYMORPHISM, HAV 4-1 PLUS/MINUS TYPE

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Oct 01, 1990

- -

Age related macular degeneration 9

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Atypical hemolytic-uremic syndrome with C3 anomaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 27, 2022

- -

Complement component 3 deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.79

DEOGEN2

Benign

0.086

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.58

MetaRNN

Benign

0.00086

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

MutationTaster

Benign

1.0

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.0

REVEL

Benign

0.020

Sift

Uncertain

0.028

Sift4G

Benign

0.11

Polyphen

0.23

Vest4

0.022

MPC

0.60

ClinPred

0.0081

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

gMVP

0.68

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over