rs2287845

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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:10

Conservation

PhyloP100: -0.712

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
C3	NM_000064.4 linkuse as main transcript	c.2863+7C>T		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 linkuse as main transcript	c.2863+7C>T		splice_region_variant, intron_variant		1	NM_000064.4	ENSP00000245907	P1

Frequencies

GnomAD3 genomes

AF:

0.660

AC:

100070

AN:

151660

Hom.:

33373

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.637

AC XY:

462804

AN XY:

726596

show subpopulations

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.:

AF XY:

0.662

AC XY:

49098

AN XY:

74148

show subpopulations

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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

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. -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over