19-6718523-T-C

Variant names:

• chr19-6718523-T-C
• rs2250656
• NM_000064.4:c.268-111A>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.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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0330
• Publications: 53 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=-0.91).
• BP6: Variant 19-6718523-T-C is Benign according to our data. Variant chr19-6718523-T-C is described in ClinVar as Benign. ClinVar VariationId is 1276044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4	c.268-111A>G		intron_variant	Intron 2 of 40	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.268-111A>G		intron_variant	Intron 2 of 40	1	NM_000064.4	ENSP00000245907.4

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

African (AFR) AF: 0.199 AC: 5595 AN: 28104

American (AMR) AF: 0.238 AC: 9723 AN: 40788

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 6285 AN: 22898

East Asian (EAS) AF: 0.228 AC: 8643 AN: 37906

South Asian (SAS) AF: 0.236 AC: 18403 AN: 77966

European-Finnish (FIN) AF: 0.328 AC: 16245 AN: 49540

Middle Eastern (MID) AF: 0.258 AC: 1323 AN: 5124

European-Non Finnish (NFE) AF: 0.288 AC: 252549 AN: 875390

Other (OTH) AF: 0.276 AC: 14077 AN: 50988

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

African (AFR) AF: 0.200 AC: 8289 AN: 41394

American (AMR) AF: 0.240 AC: 3663 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 976 AN: 3470

East Asian (EAS) AF: 0.242 AC: 1247 AN: 5146

South Asian (SAS) AF: 0.222 AC: 1069 AN: 4814

European-Finnish (FIN) AF: 0.339 AC: 3575 AN: 10536

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.280 AC: 19028 AN: 67930

Other (OTH) AF: 0.273 AC: 576 AN: 2108

Alfa AF: 0.270 Hom.: 18564

Bravo AF: 0.247

Asia WGS AF: 0.285 AC: 989 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Jun 18, 2021

GeneDx

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	-0.91
CADD	Benign	4.9
DANN	Benign	0.28
PhyloP100		-0.033
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: rs2250656; hg19: chr19-6718534; COSMIC: COSV55572097; COSMIC: COSV55572097;