chr19-6678019-T-G

Position:

chr19-6678019-T-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

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. 12/21 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:8

Conservation

PhyloP100: 0.709

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 -10 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=0.06986827).

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 id is 330271.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=4, Benign=1}. Variant chr19-6678019-T-G is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C3	NM_000064.4 linkuse as main transcript	c.4855A>C	p.Ser1619Arg	missense_variant	41/41	ENST00000245907.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C3	ENST00000245907.11 linkuse as main transcript	c.4855A>C	p.Ser1619Arg	missense_variant	41/41	1	NM_000064.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00136

AC:

207

AN:

151960

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00118

AC:

298

AN:

251478

Hom.:

AF XY:

0.00116

AC XY:

157

AN XY:

135916

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.00192

AC XY:

1399

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.000760

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00250

Gnomad4 OTH exome

AF:

0.00113

GnomAD4 genome

AF:

0.00136

AC:

207

AN:

152078

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000983

Gnomad4 ASJ

AF:

0.000866

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00252

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.00207

Hom.:

Bravo

AF:

0.00149

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00110

AC:

133

EpiCase

AF:

0.00202

EpiControl

AF:

0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2019	Published functional studies demonstrate no significant impact on expression, secretion, hemolytic activity or other functional properties (Mohlin et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23847193, 30131807, 29888403, 24029428, 24736606, 28852487, 28911789, 27939104, 27013439, 26638553) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	C3: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Complement component 3 deficiency

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 01, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 17, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 22, 2023	Variant summary: C3 c.4855A>C (p.Ser1619Arg) results in a non-conservative amino acid change located in the Netrin domain (IPR001134) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 1613968 control chromosomes, predominantly at a frequency of 0.0025 within the Non-Finnish European subpopulation in the gnomAD database, including 4 homozygotes. c.4855A>C has been reported in the literature in individuals affected with Hemolytic Uremic Syndrome (Bu_2014, Feng_2013), Glomerulopathy (Haydock_2022) and recurrent pregnancy loss (Mohlin_2018) without evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hemolytic Uremic Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Mohlin_2018). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 24029428, 23847193, 34714369, 30131807). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014and classified as benign/likely benign (n=5) and VUS (n=4). Based on the evidence outlined above, the variant was classified as likely benign. -

Age related macular degeneration 9;C2752037:Atypical hemolytic-uremic syndrome with C3 anomaly;C3151071:Complement component 3 deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

C3 NM_000064.3 exon 41 p.Ser1619Arg (c.4855A>C): This variant has been reported in the literature in at least 1 individual with atypical hemolytic uremic syndrome (aHUS) (Feng 2013 PMID:23847193, Bu 2014 PMID:24029428) as well as recurrent pregnancy loss (Mohlin 2018 PMID:30131807). This variant has also been reported in individuals with age-related macular degeneration; however, at least 1 of these publications suggest that this variant may not be associated with this presentation (Duvvari 2014 PMID:24736606, Geerlings 2018 PMID:29888403). This variant is present in 0.2% (278/129150) of European alleles including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/19-6678030-T-G?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:330271). This variant amino acid Arginine (Arg) is present in 4 species (Squirrel, Pika, Ferret, Cavefish) and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

C3-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 02, 2024

The C3 c.4855A>C variant is predicted to result in the amino acid substitution p.Ser1619Arg. This variant has been reported in individuals in the heterozygous state, and along with the CFH c.3583G>T (p.Glu1195X) variant, with atypical hemolytic uremic syndrome (Supplemental Table 2, Patient 11, Bu et al. 2013. PubMed ID: 24029428; Patient ID MA-7, Feng et al. 2013. PubMed ID: 23847193; Dowen et al. 2017. PubMed ID: 28852487; Table S3, Geerlings et al. 2018. PubMed ID: 29888403; Huerta et al. 2018. PubMed ID: 28911789). This variant has also been reported in the heterozygous state in individuals with age-related macular degeneration (AMD) (Duvvari et al. 2014. PubMed ID: 24736606; Huerta et al. 2018. PubMed ID: 28911789, Table S3, Geerlings et al. 2018. PubMed ID: 29888403) and in an individual with spontaneous pregnancy loss (Mohlin et al. 2018. PubMed ID: 30131807). Of note, this variant was also reported in control populations (Duvvari et al. 2014. PubMed ID: 24736606; Huerta et al. 2018. PubMed ID: 28911789; Mohlin et al. 2018. PubMed ID: 30131807). This variant is reported in 0.22% of alleles in individuals, including one homozygote, of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding it pathogenicity in ClinVar, ranging from uncertain significance to likely benign to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/330271/). While this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Age related macular degeneration 9

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Atypical hemolytic-uremic syndrome with C3 anomaly

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.63

M_CAP

Benign

0.074

MetaRNN

Benign

0.070

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

0.95

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.7

REVEL

Benign

0.051

Sift

Benign

0.097

Sift4G

Benign

0.15

Polyphen

0.83

Vest4

0.67

MutPred

0.35

Loss of methylation at K1615 (P = 0.0641);

MVP

0.57

MPC

0.74

ClinPred

0.020

GERP RS

4.0

Varity_R

0.45

gMVP

0.83

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

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