19-6678742-A-G

Variant names:

• chr19-6678742-A-G
• rs11569562
• NM_000064.4:c.4631-287T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000064.4(C3):​c.4631-287T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 151,808 control chromosomes in the GnomAD database, including 19,057 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.50 (19057 hom., cov: 31)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.947
• Publications: 19 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

ENSG00000297005 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-6678742-A-G is Benign according to our data. Variant chr19-6678742-A-G is described in ClinVar as Benign. ClinVar VariationId is 1181127.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000064.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	NM_000064.4	MANE Select	c.4631-287T>C		intron	N/A	NP_000055.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	ENST00000245907.11	TSL:1 MANE Select	c.4631-287T>C		intron	N/A	ENSP00000245907.4
	C3	ENST00000695654.1		c.3656-287T>C		intron	N/A	ENSP00000512085.1
	C3	ENST00000695653.1		c.2540-287T>C		intron	N/A	ENSP00000512084.1

Frequencies

GnomAD3 genomes AF: 0.499 AC: 75628 AN: 151692 Hom.: 19053 Cov.: 31

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.521

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.538

Gnomad SAS AF: 0.592

Gnomad FIN AF: 0.490

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.513

Gnomad OTH AF: 0.524

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.498 AC: 75645 AN: 151808 Hom.: 19057 Cov.: 31 AF XY: 0.499 AC XY: 36993 AN XY: 74178

African (AFR) AF: 0.453 AC: 18716 AN: 41330

American (AMR) AF: 0.521 AC: 7946 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 1592 AN: 3466

East Asian (EAS) AF: 0.537 AC: 2776 AN: 5170

South Asian (SAS) AF: 0.591 AC: 2846 AN: 4816

European-Finnish (FIN) AF: 0.490 AC: 5160 AN: 10536

Middle Eastern (MID) AF: 0.551 AC: 161 AN: 292

European-Non Finnish (NFE) AF: 0.513 AC: 34880 AN: 67936

Other (OTH) AF: 0.523 AC: 1101 AN: 2106

Alfa AF: 0.511 Hom.: 83640

Bravo AF: 0.499

Asia WGS AF: 0.572 AC: 1991 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.92
DANN	Benign	0.45
PhyloP100		-0.95
PromoterAI		0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs11569562; hg19: chr19-6678753;