chr19-6685293-G-C

Variant names:

• chr19-6685293-G-C
• rs2241393
• NM_000064.4:c.3811-147C>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.3811-147C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 739,252 control chromosomes in the GnomAD database, including 61,215 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11067 hom., cov: 31)
  • Exomes 𝑓: 0.40 (50148 hom.)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.503
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-6685293-G-C is Benign according to our data. Variant chr19-6685293-G-C is described in ClinVar as Benign. ClinVar VariationId is 1261016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.613 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4	c.3811-147C>G		intron_variant	Intron 29 of 40	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.3811-147C>G		intron_variant	Intron 29 of 40	1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56864 AN: 151844 Hom.: 11050 Cov.: 31

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.410

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.333

Gnomad EAS AF: 0.631

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.478

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.366

GnomAD4 exome AF: 0.403 AC: 236758 AN: 587288 Hom.: 50148 AF XY: 0.404 AC XY: 127330 AN XY: 315144

African (AFR) AF: 0.296 AC: 4810 AN: 16248

American (AMR) AF: 0.405 AC: 13916 AN: 34346

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 6596 AN: 19988

East Asian (EAS) AF: 0.669 AC: 21494 AN: 32126

South Asian (SAS) AF: 0.451 AC: 28156 AN: 62382

European-Finnish (FIN) AF: 0.469 AC: 17606 AN: 37532

Middle Eastern (MID) AF: 0.328 AC: 868 AN: 2648

European-Non Finnish (NFE) AF: 0.374 AC: 131062 AN: 350546

Other (OTH) AF: 0.389 AC: 12250 AN: 31472

GnomAD4 genome AF: 0.375 AC: 56935 AN: 151964 Hom.: 11067 Cov.: 31 AF XY: 0.382 AC XY: 28360 AN XY: 74252

African (AFR) AF: 0.298 AC: 12367 AN: 41450

American (AMR) AF: 0.383 AC: 5835 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 1155 AN: 3470

East Asian (EAS) AF: 0.631 AC: 3265 AN: 5176

South Asian (SAS) AF: 0.446 AC: 2150 AN: 4820

European-Finnish (FIN) AF: 0.478 AC: 5044 AN: 10548

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.381 AC: 25885 AN: 67930

Other (OTH) AF: 0.372 AC: 785 AN: 2112

Alfa AF: 0.379 Hom.: 6336

Bravo AF: 0.368

Asia WGS AF: 0.507 AC: 1760 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.0
DANN	Benign	0.43
PhyloP100		0.50
PromoterAI		-0.014	Neutral
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: rs2241393; hg19: chr19-6685304; COSMIC: COSV55574677; COSMIC: COSV55574677;