rs2277984

Positions:

• chr19-6679500-C-T

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.4457-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 1,601,234 control chromosomes in the GnomAD database, including 215,132 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 0.50 (19021 hom., cov: 32)
  • Exomes 𝑓: 0.52 (196111 hom.)
• Consequence: C3 NM_000064.4 splice_region, intron
• Scores: Splicing: ADA: 0.00004986
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -4.69

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-6679500-C-T is Benign according to our data. Variant chr19-6679500-C-T is described in ClinVar as [Benign]. Clinvar id is 330282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6679500-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C3	NM_000064.4	c.4457-4G>A		splice_region_variant, intron_variant		ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.4457-4G>A		splice_region_variant, intron_variant		1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75599 AN: 151822 Hom.: 19016 Cov.: 32

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.521

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.535

Gnomad SAS AF: 0.592

Gnomad FIN AF: 0.490

Gnomad MID AF: 0.545

Gnomad NFE AF: 0.513

Gnomad OTH AF: 0.525

GnomAD3 exomes AF: 0.522 AC: 131296 AN: 251356 Hom.: 34538 AF XY: 0.526 AC XY: 71500 AN XY: 135856

Gnomad AFR exome AF: 0.453

Gnomad AMR exome AF: 0.510

Gnomad ASJ exome AF: 0.464

Gnomad EAS exome AF: 0.550

Gnomad SAS exome AF: 0.597

Gnomad FIN exome AF: 0.500

Gnomad NFE exome AF: 0.521

Gnomad OTH exome AF: 0.516

GnomAD4 exome AF: 0.518 AC: 750911 AN: 1449294 Hom.: 196111 Cov.: 31 AF XY: 0.520 AC XY: 375296 AN XY: 721674

Gnomad4 AFR exome AF: 0.451

Gnomad4 AMR exome AF: 0.516

Gnomad4 ASJ exome AF: 0.457

Gnomad4 EAS exome AF: 0.520

Gnomad4 SAS exome AF: 0.595

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.516

Gnomad4 OTH exome AF: 0.517

GnomAD4 genome AF: 0.498 AC: 75618 AN: 151940 Hom.: 19021 Cov.: 32 AF XY: 0.498 AC XY: 36990 AN XY: 74270

Gnomad4 AFR AF: 0.452

Gnomad4 AMR AF: 0.521

Gnomad4 ASJ AF: 0.459

Gnomad4 EAS AF: 0.535

Gnomad4 SAS AF: 0.591

Gnomad4 FIN AF: 0.490

Gnomad4 NFE AF: 0.513

Gnomad4 OTH AF: 0.524

Alfa AF: 0.514 Hom.: 30569

Bravo AF: 0.499

Asia WGS AF: 0.571 AC: 1987 AN: 3478

EpiCase AF: 0.520

EpiControl AF: 0.524

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

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

Age related macular degeneration 9 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Complement component 3 deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Atypical hemolytic-uremic syndrome with C3 anomaly Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.83
CADD	Benign	0.14
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000050
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: rs2277984; hg19: chr19-6679511; COSMIC: COSV55579365; COSMIC: COSV55579365;