19-6697395-A-G

Variant summary

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

The NM_000064.4(C3):ā€‹c.2745T>Cā€‹(p.Ala915Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.768 in 1,613,598 control chromosomes in the GnomAD database, including 477,870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.77 ( 45275 hom., cov: 29)
Exomes š‘“: 0.77 ( 432595 hom. )

Consequence

C3
NM_000064.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -5.36
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=-0.94).
BP6
Variant 19-6697395-A-G is Benign according to our data. Variant chr19-6697395-A-G is described in ClinVar as [Benign]. Clinvar id is 330300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6697395-A-G is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-5.36 with no splicing effect.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.892 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
C3NM_000064.4 linkuse as main transcriptc.2745T>C p.Ala915Ala synonymous_variant 21/41 ENST00000245907.11 NP_000055.2 P01024V9HWA9B4DR57

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
C3ENST00000245907.11 linkuse as main transcriptc.2745T>C p.Ala915Ala synonymous_variant 21/411 NM_000064.4 ENSP00000245907.4 P01024

Frequencies

GnomAD3 genomes
AF:
0.772
AC:
117094
AN:
151768
Hom.:
45236
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.758
Gnomad AMI
AF:
0.610
Gnomad AMR
AF:
0.842
Gnomad ASJ
AF:
0.813
Gnomad EAS
AF:
0.914
Gnomad SAS
AF:
0.813
Gnomad FIN
AF:
0.758
Gnomad MID
AF:
0.766
Gnomad NFE
AF:
0.752
Gnomad OTH
AF:
0.800
GnomAD3 exomes
AF:
0.797
AC:
200347
AN:
251438
Hom.:
80256
AF XY:
0.793
AC XY:
107791
AN XY:
135888
show subpopulations
Gnomad AFR exome
AF:
0.756
Gnomad AMR exome
AF:
0.893
Gnomad ASJ exome
AF:
0.797
Gnomad EAS exome
AF:
0.911
Gnomad SAS exome
AF:
0.812
Gnomad FIN exome
AF:
0.758
Gnomad NFE exome
AF:
0.758
Gnomad OTH exome
AF:
0.803
GnomAD4 exome
AF:
0.768
AC:
1122592
AN:
1461712
Hom.:
432595
Cov.:
55
AF XY:
0.768
AC XY:
558550
AN XY:
727166
show subpopulations
Gnomad4 AFR exome
AF:
0.761
Gnomad4 AMR exome
AF:
0.887
Gnomad4 ASJ exome
AF:
0.795
Gnomad4 EAS exome
AF:
0.929
Gnomad4 SAS exome
AF:
0.807
Gnomad4 FIN exome
AF:
0.754
Gnomad4 NFE exome
AF:
0.754
Gnomad4 OTH exome
AF:
0.778
GnomAD4 genome
AF:
0.772
AC:
117188
AN:
151886
Hom.:
45275
Cov.:
29
AF XY:
0.775
AC XY:
57530
AN XY:
74240
show subpopulations
Gnomad4 AFR
AF:
0.758
Gnomad4 AMR
AF:
0.843
Gnomad4 ASJ
AF:
0.813
Gnomad4 EAS
AF:
0.914
Gnomad4 SAS
AF:
0.812
Gnomad4 FIN
AF:
0.758
Gnomad4 NFE
AF:
0.752
Gnomad4 OTH
AF:
0.797
Alfa
AF:
0.765
Hom.:
103369
Bravo
AF:
0.780
Asia WGS
AF:
0.845
AC:
2938
AN:
3478
EpiCase
AF:
0.771
EpiControl
AF:
0.778

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxNov 10, 2018- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
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 12, 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 testingIllumina Laboratory Services, IlluminaJan 12, 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- -
Atypical hemolytic-uremic syndrome with C3 anomaly Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 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
-0.94
CADD
Benign
0.068
DANN
Benign
0.25

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: rs423490; hg19: chr19-6697406; COSMIC: COSV55580035; COSMIC: COSV55580035; API