19-6678019-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:8
• Conservation: PhyloP100: 0.709

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, C3
• 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: {Uncertain_significance=4, Likely_benign=5, 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C3	NM_000064.4	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	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.: 1 Cov.: 32

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.: 1 AF XY: 0.00116 AC XY: 157 AN XY: 135916

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.: 3 Cov.: 35 AF XY: 0.00192 AC XY: 1399 AN XY: 727244

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.: 1 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74336

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.: 1

Bravo AF: 0.00149

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00110 AC: 133

EpiCase AF: 0.00202

EpiControl AF: 0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

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	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	C3: BP4 -
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	Invitae	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Complement component 3 deficiency Uncertain:2

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. -
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]. -

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. -

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	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	0.95	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.051
Sift	Benign	0.097	T
Sift4G	Benign	0.15	T
Polyphen		0.83	P
Vest4		0.67
MutPred		0.35		Loss of methylation at K1615 (P = 0.0641);
MVP		0.57
MPC		0.74
ClinPred		0.020	T
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

Other links and lift over

dbSNP: rs2230210; hg19: chr19-6678030;