rs1389623

Variant names:

• chr19-6684186-G-A
• rs1389623
• NM_000064.4:c.4172+202C>T

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.4172+202C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 668,114 control chromosomes in the GnomAD database, including 5,247 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1857 hom., cov: 32)
  • Exomes 𝑓: 0.11 (3390 hom.)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.274
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-6684186-G-A is Benign according to our data. Variant chr19-6684186-G-A is described in ClinVar as Benign. ClinVar VariationId is 1277371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4	c.4172+202C>T		intron_variant	Intron 33 of 40	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.4172+202C>T		intron_variant	Intron 33 of 40	1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22054 AN: 152136 Hom.: 1847 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.0985

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.125

GnomAD4 exome AF: 0.112 AC: 57631 AN: 515860 Hom.: 3390 Cov.: 4 AF XY: 0.110 AC XY: 30566 AN XY: 276852

African (AFR) AF: 0.231 AC: 3535 AN: 15278

American (AMR) AF: 0.0849 AC: 2759 AN: 32494

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 1973 AN: 17288

East Asian (EAS) AF: 0.0887 AC: 2844 AN: 32074

South Asian (SAS) AF: 0.104 AC: 5931 AN: 57074

European-Finnish (FIN) AF: 0.128 AC: 4347 AN: 33866

Middle Eastern (MID) AF: 0.111 AC: 246 AN: 2220

European-Non Finnish (NFE) AF: 0.110 AC: 32610 AN: 296790

Other (OTH) AF: 0.118 AC: 3386 AN: 28776

GnomAD4 genome AF: 0.145 AC: 22102 AN: 152254 Hom.: 1857 Cov.: 32 AF XY: 0.143 AC XY: 10645 AN XY: 74458

African (AFR) AF: 0.233 AC: 9672 AN: 41528

American (AMR) AF: 0.112 AC: 1707 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 394 AN: 3472

East Asian (EAS) AF: 0.0979 AC: 508 AN: 5188

South Asian (SAS) AF: 0.106 AC: 509 AN: 4824

European-Finnish (FIN) AF: 0.120 AC: 1276 AN: 10606

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7628 AN: 68024

Other (OTH) AF: 0.128 AC: 270 AN: 2112

Alfa AF: 0.120 Hom.: 2314

Bravo AF: 0.148

Asia WGS AF: 0.0930 AC: 325 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	-0.91
CADD	Benign	1.0
DANN	Benign	0.36
PhyloP100		-0.27
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: rs1389623; hg19: chr19-6684197;