19-6697818-G-T

Variant names:

• chr19-6697818-G-T
• rs366510
• NM_000064.4:c.2441-24C>A

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.2441-24C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.638 in 1,604,534 control chromosomes in the GnomAD database, including 330,681 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33347 hom., cov: 28)
  • Exomes 𝑓: 0.64 (297334 hom.)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.54
• Publications: 22 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=-0.83).
• BP6: Variant 19-6697818-G-T is Benign according to our data. Variant chr19-6697818-G-T is described in ClinVar as Benign. ClinVar VariationId is 1192552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.82 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4	c.2441-24C>A		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.2441-24C>A		intron_variant	Intron 19 of 40	1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.660 AC: 99912 AN: 151486 Hom.: 33309 Cov.: 28

Gnomad AFR AF: 0.706

Gnomad AMI AF: 0.439

Gnomad AMR AF: 0.736

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.840

Gnomad SAS AF: 0.714

Gnomad FIN AF: 0.568

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.616

Gnomad OTH AF: 0.677

GnomAD2 exomes AF: 0.671 AC: 160972 AN: 239922 AF XY: 0.663

Gnomad AFR exome AF: 0.702

Gnomad AMR exome AF: 0.809

Gnomad ASJ exome AF: 0.596

Gnomad EAS exome AF: 0.836

Gnomad FIN exome AF: 0.563

Gnomad NFE exome AF: 0.614

Gnomad OTH exome AF: 0.662

GnomAD4 exome AF: 0.636 AC: 924179 AN: 1452930 Hom.: 297334 Cov.: 39 AF XY: 0.636 AC XY: 459563 AN XY: 722256

African (AFR) AF: 0.713 AC: 23706 AN: 33234

American (AMR) AF: 0.798 AC: 34841 AN: 43646

Ashkenazi Jewish (ASJ) AF: 0.592 AC: 15404 AN: 26000

East Asian (EAS) AF: 0.865 AC: 34127 AN: 39452

South Asian (SAS) AF: 0.706 AC: 60242 AN: 85362

European-Finnish (FIN) AF: 0.566 AC: 29903 AN: 52822

Middle Eastern (MID) AF: 0.686 AC: 3089 AN: 4506

European-Non Finnish (NFE) AF: 0.617 AC: 683999 AN: 1107914

Other (OTH) AF: 0.648 AC: 38868 AN: 59994

GnomAD4 genome AF: 0.660 AC: 100006 AN: 151604 Hom.: 33347 Cov.: 28 AF XY: 0.662 AC XY: 49024 AN XY: 74084

African (AFR) AF: 0.707 AC: 29186 AN: 41294

American (AMR) AF: 0.736 AC: 11203 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 2128 AN: 3470

East Asian (EAS) AF: 0.841 AC: 4320 AN: 5138

South Asian (SAS) AF: 0.713 AC: 3414 AN: 4788

European-Finnish (FIN) AF: 0.568 AC: 5972 AN: 10522

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

European-Non Finnish (NFE) AF: 0.615 AC: 41775 AN: 67872

Other (OTH) AF: 0.672 AC: 1411 AN: 2100

Alfa AF: 0.633 Hom.: 42179

Bravo AF: 0.675

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

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	-0.83
CADD	Benign	0.055
DANN	Benign	0.56
PhyloP100		-4.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs366510; hg19: chr19-6697829;