rs2287845

Positions:

• chr19-6696586-G-A
• chr19-6696586-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000064.4(C3):​c.2863+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.639 in 1,612,156 control chromosomes in the GnomAD database, including 332,996 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33415 hom., cov: 30)
  • Exomes 𝑓: 0.64 (299581 hom.)
• Consequence: C3 NM_000064.4 splice_region, intron
• Scores: Splicing: ADA: 0.0005128
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.712

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-6696586-G-A is Benign according to our data. Variant chr19-6696586-G-A is described in ClinVar as [Benign]. Clinvar id is 330297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6696586-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C3	NM_000064.4	c.2863+7C>T		splice_region_variant, intron_variant		ENST00000245907.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C3	ENST00000245907.11	c.2863+7C>T		splice_region_variant, intron_variant		1	NM_000064.4	P1

Frequencies

GnomAD3 genomes AF: 0.660 AC: 100070 AN: 151660 Hom.: 33373 Cov.: 30

Gnomad AFR AF: 0.706

Gnomad AMI AF: 0.443

Gnomad AMR AF: 0.736

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.842

Gnomad SAS AF: 0.713

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.616

Gnomad OTH AF: 0.676

GnomAD3 exomes AF: 0.674 AC: 169368 AN: 251462 Hom.: 58205 AF XY: 0.666 AC XY: 90563 AN XY: 135906

Gnomad AFR exome AF: 0.707

Gnomad AMR exome AF: 0.811

Gnomad ASJ exome AF: 0.597

Gnomad EAS exome AF: 0.838

Gnomad SAS exome AF: 0.709

Gnomad FIN exome AF: 0.566

Gnomad NFE exome AF: 0.618

Gnomad OTH exome AF: 0.664

GnomAD4 exome AF: 0.637 AC: 929802 AN: 1460380 Hom.: 299581 Cov.: 40 AF XY: 0.637 AC XY: 462804 AN XY: 726596

Gnomad4 AFR exome AF: 0.714

Gnomad4 AMR exome AF: 0.800

Gnomad4 ASJ exome AF: 0.593

Gnomad4 EAS exome AF: 0.865

Gnomad4 SAS exome AF: 0.706

Gnomad4 FIN exome AF: 0.567

Gnomad4 NFE exome AF: 0.618

Gnomad4 OTH exome AF: 0.648

GnomAD4 genome AF: 0.660 AC: 100168 AN: 151776 Hom.: 33415 Cov.: 30 AF XY: 0.662 AC XY: 49098 AN XY: 74148

Gnomad4 AFR AF: 0.707

Gnomad4 AMR AF: 0.737

Gnomad4 ASJ AF: 0.613

Gnomad4 EAS AF: 0.842

Gnomad4 SAS AF: 0.711

Gnomad4 FIN AF: 0.569

Gnomad4 NFE AF: 0.616

Gnomad4 OTH AF: 0.673

Alfa AF: 0.636 Hom.: 39063

Bravo AF: 0.675

Asia WGS AF: 0.771 AC: 2680 AN: 3478

EpiCase AF: 0.634

EpiControl AF: 0.633

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Age related macular degeneration 9 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Complement component 3 deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
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. -

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
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.51
DANN	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00051
dbscSNV1_RF	Benign	0.0
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: rs2287845; hg19: chr19-6696597; COSMIC: COSV55580011; COSMIC: COSV55580011;