rs1389623

Positions:

• chr19-6684186-G-A

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.4172+202C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 668,114 control chromosomes in the GnomAD database, including 5,247 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1857 hom., cov: 32)
  • Exomes 𝑓: 0.11 (3390 hom.)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.274

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=-0.91).
• BP6: Variant 19-6684186-G-A is Benign according to our data. Variant chr19-6684186-G-A is described in ClinVar as [Benign]. Clinvar id is 1277371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C3	NM_000064.4	c.4172+202C>T		intron_variant		ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.4172+202C>T		intron_variant		1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22054 AN: 152136 Hom.: 1847 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.0985

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.125

GnomAD4 exome AF: 0.112 AC: 57631 AN: 515860 Hom.: 3390 Cov.: 4 AF XY: 0.110 AC XY: 30566 AN XY: 276852

Gnomad4 AFR exome AF: 0.231

Gnomad4 AMR exome AF: 0.0849

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.0887

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.128

Gnomad4 NFE exome AF: 0.110

Gnomad4 OTH exome AF: 0.118

GnomAD4 genome AF: 0.145 AC: 22102 AN: 152254 Hom.: 1857 Cov.: 32 AF XY: 0.143 AC XY: 10645 AN XY: 74458

Gnomad4 AFR AF: 0.233

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.0979

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.120

Gnomad4 NFE AF: 0.112

Gnomad4 OTH AF: 0.128

Alfa AF: 0.116 Hom.: 1478

Bravo AF: 0.148

Asia WGS AF: 0.0930 AC: 325 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.0
DANN	Benign	0.36

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: rs1389623; hg19: chr19-6684197;