chr19-6697395-A-G

Position:

• chr19-6697395-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000064.4(C3):​c.2745T>C​(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45275 hom., cov: 29)
  • Exomes 𝑓: 0.77 (432595 hom.)
• Consequence: C3 NM_000064.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -5.36

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 -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
C3	NM_000064.4	c.2745T>C	p.Ala915Ala	synonymous_variant	21/41	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.2745T>C	p.Ala915Ala	synonymous_variant	21/41	1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.772 AC: 117094 AN: 151768 Hom.: 45236 Cov.: 29

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

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

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

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

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	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	-0.94
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

Other links and lift over

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