19-6677978-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000064.4(C3):​c.4896C>T​(p.Pro1632=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 1,613,702 control chromosomes in the GnomAD database, including 217,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 19802 hom., cov: 31)
Exomes 𝑓: 0.52 ( 197895 hom. )

Consequence

C3
NM_000064.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -6.82
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
Variant 19-6677978-G-A is Benign according to our data. Variant chr19-6677978-G-A is described in ClinVar as [Benign]. Clinvar id is 330270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6677978-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-6.82 with no splicing effect.
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
C3NM_000064.4 linkuse as main transcriptc.4896C>T p.Pro1632= synonymous_variant 41/41 ENST00000245907.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
C3ENST00000245907.11 linkuse as main transcriptc.4896C>T p.Pro1632= synonymous_variant 41/411 NM_000064.4 P1

Frequencies

GnomAD3 genomes
AF:
0.509
AC:
77195
AN:
151750
Hom.:
19799
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.492
Gnomad AMI
AF:
0.512
Gnomad AMR
AF:
0.525
Gnomad ASJ
AF:
0.459
Gnomad EAS
AF:
0.536
Gnomad SAS
AF:
0.587
Gnomad FIN
AF:
0.488
Gnomad MID
AF:
0.551
Gnomad NFE
AF:
0.513
Gnomad OTH
AF:
0.529
GnomAD3 exomes
AF:
0.524
AC:
131855
AN:
251460
Hom.:
34805
AF XY:
0.527
AC XY:
71659
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.494
Gnomad AMR exome
AF:
0.511
Gnomad ASJ exome
AF:
0.464
Gnomad EAS exome
AF:
0.548
Gnomad SAS exome
AF:
0.594
Gnomad FIN exome
AF:
0.499
Gnomad NFE exome
AF:
0.521
Gnomad OTH exome
AF:
0.516
GnomAD4 exome
AF:
0.519
AC:
758850
AN:
1461834
Hom.:
197895
Cov.:
59
AF XY:
0.521
AC XY:
378656
AN XY:
727218
show subpopulations
Gnomad4 AFR exome
AF:
0.495
Gnomad4 AMR exome
AF:
0.518
Gnomad4 ASJ exome
AF:
0.457
Gnomad4 EAS exome
AF:
0.518
Gnomad4 SAS exome
AF:
0.592
Gnomad4 FIN exome
AF:
0.500
Gnomad4 NFE exome
AF:
0.517
Gnomad4 OTH exome
AF:
0.519
GnomAD4 genome
AF:
0.508
AC:
77213
AN:
151868
Hom.:
19802
Cov.:
31
AF XY:
0.508
AC XY:
37712
AN XY:
74190
show subpopulations
Gnomad4 AFR
AF:
0.491
Gnomad4 AMR
AF:
0.525
Gnomad4 ASJ
AF:
0.459
Gnomad4 EAS
AF:
0.535
Gnomad4 SAS
AF:
0.586
Gnomad4 FIN
AF:
0.488
Gnomad4 NFE
AF:
0.513
Gnomad4 OTH
AF:
0.528
Alfa
AF:
0.510
Hom.:
14109
Bravo
AF:
0.511
Asia WGS
AF:
0.573
AC:
1995
AN:
3478
EpiCase
AF:
0.519
EpiControl
AF:
0.524

ClinVar

Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Age related macular degeneration 9 Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 submitterclinical testingGenome-Nilou LabJul 14, 2021- -
Complement component 3 deficiency Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 14, 2021- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Atypical hemolytic-uremic syndrome with C3 anomaly Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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
-0.85
CADD
Benign
0.0040
DANN
Benign
0.76
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
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.

Other links and lift over

dbSNP: rs17030; hg19: chr19-6677989; COSMIC: COSV55570961; COSMIC: COSV55570961; API