rs433594

Variant names:

• chr19-6702031-A-G
• rs433594
• NM_000064.4:c.2440+96T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-6702031-A-G
• chr19-6702031-A-C
• chr19-6702031-A-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.2440+96T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.652 in 771,894 control chromosomes in the GnomAD database, including 166,876 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33390 hom., cov: 31)
  • Exomes 𝑓: 0.65 (133486 hom.)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.36
• Publications: 10 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: ClinGen, Labcorp Genetics (formerly Invitae)
• complement component 3 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet
• 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=-0.85).
• BP6: Variant 19-6702031-A-G is Benign according to our data. Variant chr19-6702031-A-G is described in ClinVar as Benign. ClinVar VariationId is 1192554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.821 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	NM_000064.4	MANE Select	c.2440+96T>C		intron	N/A	NP_000055.2	P01024

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	ENST00000245907.11	TSL:1 MANE Select	c.2440+96T>C		intron	N/A	ENSP00000245907.4	P01024
	C3	ENST00000952696.1		c.2452+96T>C		intron	N/A	ENSP00000622755.1
	C3	ENST00000879543.1		c.2440+96T>C		intron	N/A	ENSP00000549602.1

Frequencies

GnomAD3 genomes AF: 0.659 AC: 100116 AN: 151886 Hom.: 33352 Cov.: 31

Gnomad AFR AF: 0.704

Gnomad AMI AF: 0.443

Gnomad AMR AF: 0.736

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.841

Gnomad SAS AF: 0.713

Gnomad FIN AF: 0.568

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.616

Gnomad OTH AF: 0.676

GnomAD4 exome AF: 0.650 AC: 402733 AN: 619890 Hom.: 133486 AF XY: 0.649 AC XY: 218698 AN XY: 337074

African (AFR) AF: 0.710 AC: 12275 AN: 17300

American (AMR) AF: 0.794 AC: 31937 AN: 40200

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 12230 AN: 20710

East Asian (EAS) AF: 0.867 AC: 30552 AN: 35234

South Asian (SAS) AF: 0.702 AC: 47769 AN: 68000

European-Finnish (FIN) AF: 0.559 AC: 22517 AN: 40264

Middle Eastern (MID) AF: 0.685 AC: 1856 AN: 2708

European-Non Finnish (NFE) AF: 0.613 AC: 222371 AN: 362652

Other (OTH) AF: 0.647 AC: 21226 AN: 32822

GnomAD4 genome AF: 0.659 AC: 100211 AN: 152004 Hom.: 33390 Cov.: 31 AF XY: 0.661 AC XY: 49136 AN XY: 74294

African (AFR) AF: 0.705 AC: 29208 AN: 41458

American (AMR) AF: 0.736 AC: 11231 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 2126 AN: 3468

East Asian (EAS) AF: 0.842 AC: 4350 AN: 5168

South Asian (SAS) AF: 0.712 AC: 3431 AN: 4822

European-Finnish (FIN) AF: 0.568 AC: 5984 AN: 10540

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

European-Non Finnish (NFE) AF: 0.616 AC: 41863 AN: 67978

Other (OTH) AF: 0.672 AC: 1417 AN: 2108

Alfa AF: 0.656 Hom.: 11001

Bravo AF: 0.675

Asia WGS AF: 0.765 AC: 2659 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Age related macular degeneration 9 (1)
-	-	1	Complement component 3 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.0
DANN	Benign	0.74
PhyloP100		-1.4
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: rs433594; hg19: chr19-6702042;