19-6718376-G-C

Position:

• chr19-6718376-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R102H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.14 (2011 hom., cov: 32)
  • Exomes 𝑓: 0.19 (29334 hom.)
• Consequence: C3 NM_000064.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.00200

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, C3
• 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	UniProt
C3	NM_000064.4	c.304C>G	p.Arg102Gly	missense_variant	3/41	ENST00000245907.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C3	ENST00000245907.11	c.304C>G	p.Arg102Gly	missense_variant	3/41	1	NM_000064.4	P1

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21517 AN: 152112 Hom.: 2011 Cov.: 32

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

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.: 38 AF XY: 0.191 AC XY: 138972 AN XY: 727206

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.: 32 AF XY: 0.139 AC XY: 10331 AN XY: 74414

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:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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. -

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. -

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	T
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	N
LIST_S2	Benign	0.38	T;T
MetaRNN	Benign	0.0028	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
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	T
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

Other links and lift over

dbSNP: rs2230199; hg19: chr19-6718387; COSMIC: COSV55573165; COSMIC: COSV55573165;