19-6709837-C-T

Position:

• chr19-6709837-C-T

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.1692G>A​(p.Val564Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 1,612,958 control chromosomes in the GnomAD database, including 86,070 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11312 hom., cov: 29)
  • Exomes 𝑓: 0.31 (74758 hom.)
• Consequence: C3 NM_000064.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.18

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=-0.6).
• BP6: Variant 19-6709837-C-T is Benign according to our data. Variant chr19-6709837-C-T is described in ClinVar as [Benign]. Clinvar id is 330321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6709837-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.17 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C3	NM_000064.4	c.1692G>A	p.Val564Val	synonymous_variant	14/41	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.1692G>A	p.Val564Val	synonymous_variant	14/41	1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56132 AN: 151510 Hom.: 11309 Cov.: 29

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.355

GnomAD3 exomes AF: 0.353 AC: 88578 AN: 251044 Hom.: 16536 AF XY: 0.349 AC XY: 47363 AN XY: 135742

Gnomad AFR exome AF: 0.535

Gnomad AMR exome AF: 0.400

Gnomad ASJ exome AF: 0.299

Gnomad EAS exome AF: 0.469

Gnomad SAS exome AF: 0.440

Gnomad FIN exome AF: 0.316

Gnomad NFE exome AF: 0.284

Gnomad OTH exome AF: 0.320

GnomAD4 exome AF: 0.313 AC: 457348 AN: 1461330 Hom.: 74758 Cov.: 45 AF XY: 0.315 AC XY: 228798 AN XY: 726966

Gnomad4 AFR exome AF: 0.532

Gnomad4 AMR exome AF: 0.397

Gnomad4 ASJ exome AF: 0.299

Gnomad4 EAS exome AF: 0.478

Gnomad4 SAS exome AF: 0.441

Gnomad4 FIN exome AF: 0.306

Gnomad4 NFE exome AF: 0.288

Gnomad4 OTH exome AF: 0.321

GnomAD4 genome AF: 0.370 AC: 56177 AN: 151628 Hom.: 11312 Cov.: 29 AF XY: 0.373 AC XY: 27640 AN XY: 74082

Gnomad4 AFR AF: 0.523

Gnomad4 AMR AF: 0.363

Gnomad4 ASJ AF: 0.304

Gnomad4 EAS AF: 0.464

Gnomad4 SAS AF: 0.431

Gnomad4 FIN AF: 0.311

Gnomad4 NFE AF: 0.284

Gnomad4 OTH AF: 0.356

Alfa AF: 0.318 Hom.: 6217

Bravo AF: 0.382

Asia WGS AF: 0.440 AC: 1527 AN: 3478

EpiCase AF: 0.278

EpiControl AF: 0.287

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2018	- -

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	- -

Complement component 3 deficiency 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	- -

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	-0.60
CADD	Benign	8.0
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2230204; hg19: chr19-6709848; COSMIC: COSV55576568; COSMIC: COSV55576568;