19-6702011-G-C

Variant names:

• chr19-6702011-G-C
• rs408290
• NM_000064.4:c.2440+116C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000064.4(C3):​c.2440+116C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 724,746 control chromosomes in the GnomAD database, including 157,618 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33387 hom., cov: 31)
  • Exomes 𝑓: 0.65 (124231 hom.)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0150
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• atypical hemolytic-uremic syndrome with C3 anomaly

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• complement component 3 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Laboratory for Molecular Medicine
• C3 glomerulonephritis

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 19-6702011-G-C is Benign according to our data. Variant chr19-6702011-G-C is described in ClinVar as Benign. ClinVar VariationId is 1192553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4	c.2440+116C>G		intron_variant	Intron 19 of 40	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.2440+116C>G		intron_variant	Intron 19 of 40	1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.659 AC: 100105 AN: 151848 Hom.: 33349 Cov.: 31

Gnomad AFR AF: 0.704

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.736

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.841

Gnomad SAS AF: 0.713

Gnomad FIN AF: 0.568

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.616

Gnomad OTH AF: 0.677

GnomAD4 exome AF: 0.652 AC: 373672 AN: 572780 Hom.: 124231 AF XY: 0.651 AC XY: 203102 AN XY: 311826

African (AFR) AF: 0.709 AC: 11561 AN: 16298

American (AMR) AF: 0.790 AC: 28747 AN: 36394

Ashkenazi Jewish (ASJ) AF: 0.590 AC: 11860 AN: 20090

East Asian (EAS) AF: 0.868 AC: 28935 AN: 33336

South Asian (SAS) AF: 0.702 AC: 45726 AN: 65168

European-Finnish (FIN) AF: 0.559 AC: 20604 AN: 36842

Middle Eastern (MID) AF: 0.694 AC: 1723 AN: 2482

European-Non Finnish (NFE) AF: 0.617 AC: 204254 AN: 330946

Other (OTH) AF: 0.649 AC: 20262 AN: 31224

GnomAD4 genome AF: 0.659 AC: 100200 AN: 151966 Hom.: 33387 Cov.: 31 AF XY: 0.662 AC XY: 49138 AN XY: 74282

African (AFR) AF: 0.705 AC: 29192 AN: 41432

American (AMR) AF: 0.737 AC: 11235 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 2127 AN: 3470

East Asian (EAS) AF: 0.842 AC: 4354 AN: 5172

South Asian (SAS) AF: 0.712 AC: 3435 AN: 4824

European-Finnish (FIN) AF: 0.568 AC: 5984 AN: 10526

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.616 AC: 41853 AN: 67976

Other (OTH) AF: 0.673 AC: 1419 AN: 2110

Alfa AF: 0.494 Hom.: 1259

Bravo AF: 0.675

Asia WGS AF: 0.765 AC: 2659 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Age related macular degeneration 9 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Complement component 3 deficiency Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.3
DANN	Benign	0.71
PhyloP100		0.015
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs408290; hg19: chr19-6702022;