rs2241394

Positions:

• chr19-6685219-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000064.4(C3):​c.3811-73C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,417,662 control chromosomes in the GnomAD database, including 11,259 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (992 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10267 hom.)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.606

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-6685219-G-C is Benign according to our data. Variant chr19-6685219-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 162178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C3	NM_000064.4	c.3811-73C>G		intron_variant		ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.3811-73C>G		intron_variant		1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15835 AN: 152048 Hom.: 989 Cov.: 32

Gnomad AFR AF: 0.0469

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.0795

Gnomad SAS AF: 0.0605

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.112

GnomAD4 exome AF: 0.123 AC: 156028 AN: 1265496 Hom.: 10267 AF XY: 0.122 AC XY: 77303 AN XY: 635006

Gnomad4 AFR exome AF: 0.0426

Gnomad4 AMR exome AF: 0.0867

Gnomad4 ASJ exome AF: 0.154

Gnomad4 EAS exome AF: 0.0762

Gnomad4 SAS exome AF: 0.0635

Gnomad4 FIN exome AF: 0.183

Gnomad4 NFE exome AF: 0.131

Gnomad4 OTH exome AF: 0.118

GnomAD4 genome AF: 0.104 AC: 15855 AN: 152166 Hom.: 992 Cov.: 32 AF XY: 0.105 AC XY: 7831 AN XY: 74386

Gnomad4 AFR AF: 0.0473

Gnomad4 AMR AF: 0.105

Gnomad4 ASJ AF: 0.161

Gnomad4 EAS AF: 0.0793

Gnomad4 SAS AF: 0.0603

Gnomad4 FIN AF: 0.181

Gnomad4 NFE AF: 0.128

Gnomad4 OTH AF: 0.111

Alfa AF: 0.118 Hom.: 161

Bravo AF: 0.0978

Asia WGS AF: 0.0630 AC: 219 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	This variant is associated with the following publications: (PMID: 22174912) -
not provided, no classification provided	not provided	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Kidney disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	11
DANN	Benign	0.56

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: rs2241394; hg19: chr19-6685230;