chr19-6677978-G-A

Position:

• chr19-6677978-G-A

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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -6.82

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]

ACMG classification

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
C3	NM_000064.4	c.4896C>T	p.Pro1632=	synonymous_variant	41/41	ENST00000245907.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C3	ENST00000245907.11	c.4896C>T	p.Pro1632=	synonymous_variant	41/41	1	NM_000064.4	P1

Frequencies

GnomAD3 genomes AF: 0.509 AC: 77195 AN: 151750 Hom.: 19799 Cov.: 31

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

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

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

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided Benign:2

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

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	-0.85
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

Other links and lift over

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