rs2250656

Positions:

• chr19-6718523-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000064.4(C3):​c.268-111A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,340,566 control chromosomes in the GnomAD database, including 52,315 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (5026 hom., cov: 30)
  • Exomes 𝑓: 0.28 (47289 hom.)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0330

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-6718523-T-C is Benign according to our data. Variant chr19-6718523-T-C is described in ClinVar as [Benign]. Clinvar id is 1276044.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C3	NM_000064.4	c.268-111A>G		intron_variant		ENST00000245907.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C3	ENST00000245907.11	c.268-111A>G		intron_variant		1	NM_000064.4	P1

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38684 AN: 151744 Hom.: 5033 Cov.: 30

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.243

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.272

GnomAD4 exome AF: 0.280 AC: 332843 AN: 1188704 Hom.: 47289 AF XY: 0.278 AC XY: 166140 AN XY: 597310

Gnomad4 AFR exome AF: 0.199

Gnomad4 AMR exome AF: 0.238

Gnomad4 ASJ exome AF: 0.274

Gnomad4 EAS exome AF: 0.228

Gnomad4 SAS exome AF: 0.236

Gnomad4 FIN exome AF: 0.328

Gnomad4 NFE exome AF: 0.288

Gnomad4 OTH exome AF: 0.276

GnomAD4 genome AF: 0.255 AC: 38701 AN: 151862 Hom.: 5026 Cov.: 30 AF XY: 0.257 AC XY: 19108 AN XY: 74212

Gnomad4 AFR AF: 0.200

Gnomad4 AMR AF: 0.240

Gnomad4 ASJ AF: 0.281

Gnomad4 EAS AF: 0.242

Gnomad4 SAS AF: 0.222

Gnomad4 FIN AF: 0.339

Gnomad4 NFE AF: 0.280

Gnomad4 OTH AF: 0.273

Alfa AF: 0.271 Hom.: 9866

Bravo AF: 0.247

Asia WGS AF: 0.285 AC: 989 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.9
DANN	Benign	0.28

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: rs2250656; hg19: chr19-6718534; COSMIC: COSV55572097; COSMIC: COSV55572097;