rs1047286

chr19-6713251-G-Achr19-6713251-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.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. 13/19 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.719

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=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	UniProt
C3	NM_000064.4	c.941C>T	p.Pro314Leu	missense_variant	9/41	ENST00000245907.11

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20348 AN: 151964 Hom.: 1874 Cov.: 31

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

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.: 35 AF XY: 0.183 AC XY: 133204 AN XY: 726968

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.: 31 AF XY: 0.131 AC XY: 9733 AN XY: 74336

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	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

- -

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. -

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	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	13
Dann	Benign	0.79
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.00086	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.020
Sift	Uncertain	0.028	D
Sift4G	Benign	0.11	T
Polyphen		0.23	B
Vest4		0.022
MPC		0.60
ClinPred		0.0081	T
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

Other links and lift over

dbSNP: rs1047286; hg19: chr19-6713262; COSMIC: COSV55573811; COSMIC: COSV55573811;