19-6718376-G-C

Position:

chr19-6718376-G-C

Variant summary

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

The NM_000064.4(C3):c.304C>G(p.Arg102Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,614,024 control chromosomes in the GnomAD database, including 31,345 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 0.14 ( 2011 hom., cov: 32)

Exomes 𝑓: 0.19 ( 29334 hom. )

Consequence

C3
NM_000064.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: -0.00200

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:

C3 (HGNC:):

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=0.0028393269).

BP6

Variant 19-6718376-G-C is Benign according to our data. Variant chr19-6718376-G-C is described in ClinVar as [Benign]. Clinvar id is 17056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6718376-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.205 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.304C>G	p.Arg102Gly	missense_variant	3/41	ENST00000245907.11	NP_000055.2	P01024V9HWA9B4DR57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11 linkuse as main transcript	c.304C>G	p.Arg102Gly	missense_variant	3/41	1	NM_000064.4	ENSP00000245907.4		P01024

Frequencies

GnomAD3 genomes

AF:

0.141

AC:

21517

AN:

152112

Hom.:

2011

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0473

Gnomad AMI

AF:

0.0647

Gnomad AMR

AF:

0.114

Gnomad ASJ

AF:

0.207

Gnomad EAS

AF:

0.000964

Gnomad SAS

AF:

0.124

Gnomad FIN

AF:

0.181

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.208

Gnomad OTH

AF:

0.141

GnomAD3 exomes

AF:

0.150

AC:

37843

AN:

251466

Hom.:

3504

AF XY:

0.155

AC XY:

21120

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.0442

Gnomad AMR exome

AF:

0.0825

Gnomad ASJ exome

AF:

0.207

Gnomad EAS exome

AF:

0.000815

Gnomad SAS exome

AF:

0.127

Gnomad FIN exome

AF:

0.175

Gnomad NFE exome

AF:

0.206

Gnomad OTH exome

AF:

0.168

GnomAD4 exome

AF:

0.192

AC:

281032

AN:

1461794

Hom.:

29334

Cov.:

AF XY:

0.191

AC XY:

138972

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.0392

Gnomad4 AMR exome

AF:

0.0848

Gnomad4 ASJ exome

AF:

0.209

Gnomad4 EAS exome

AF:

0.000655

Gnomad4 SAS exome

AF:

0.130

Gnomad4 FIN exome

AF:

0.180

Gnomad4 NFE exome

AF:

0.214

Gnomad4 OTH exome

AF:

0.185

GnomAD4 genome

AF:

0.141

AC:

21521

AN:

152230

Hom.:

2011

Cov.:

AF XY:

0.139

AC XY:

10331

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.0473

Gnomad4 AMR

AF:

0.114

Gnomad4 ASJ

AF:

0.207

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.126

Gnomad4 FIN

AF:

0.181

Gnomad4 NFE

AF:

0.208

Gnomad4 OTH

AF:

0.139

Alfa

AF:

0.198

Hom.:

2614

Bravo

AF:

0.131

ESP6500AA

AF:

0.0481

AC:

212

ESP6500EA

AF:

0.209

AC:

1801

ExAC

AF:

0.152

AC:

18427

Asia WGS

AF:

0.0590

AC:

207

AN:

3478

EpiCase

AF:

0.209

EpiControl

AF:

0.205

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

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: 29485352, 30131807, 25322978, 7870343, 20385819, 21555552, 24736606, 19823576, 19168221, 17634448, 24036950, 24036949, 20664795, 25488663, 21784901, 18325906, 25688879, 25087612) -

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. -

C3S/C3F POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Apr 01, 2013

- -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 27, 2022

- -

MACULAR DEGENERATION, AGE-RELATED, 9, SUSCEPTIBILITY TO

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.54

CADD

Benign

9.9

DANN

Benign

0.56

DEOGEN2

Benign

0.080

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.38

T;T

MetaRNN

Benign

0.0028

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.20

N;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.7

N;.

REVEL

Benign

0.068

Sift

Benign

0.40

T;.

Sift4G

Benign

0.38

T;.

Polyphen

0.0

B;.

Vest4

0.034

MPC

0.75

ClinPred

0.0036

GERP RS

-0.59

Varity_R

0.59

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

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

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