19-6679500-C-T

Variant names:

• chr19-6679500-C-T
• rs2277984
• NM_000064.4:c.4457-4G>A

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.4457-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 1,601,234 control chromosomes in the GnomAD database, including 215,132 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19021 hom., cov: 32)
  • Exomes 𝑓: 0.52 (196111 hom.)
• Consequence: C3 NM_000064.4 splice_region, intron
• Scores: Splicing: ADA: 0.00004986
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -4.69
• Publications: 38 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

ENSG00000297005 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-6679500-C-T is Benign according to our data. Variant chr19-6679500-C-T is described in ClinVar as Benign. ClinVar VariationId is 330282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	NM_000064.4	MANE Select	c.4457-4G>A		splice_region 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.4457-4G>A		splice_region intron	N/A	ENSP00000245907.4	P01024
	C3	ENST00000952696.1		c.4469-4G>A		splice_region intron	N/A	ENSP00000622755.1
	C3	ENST00000879543.1		c.4454-4G>A		splice_region intron	N/A	ENSP00000549602.1

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75599 AN: 151822 Hom.: 19016 Cov.: 32

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.521

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.535

Gnomad SAS AF: 0.592

Gnomad FIN AF: 0.490

Gnomad MID AF: 0.545

Gnomad NFE AF: 0.513

Gnomad OTH AF: 0.525

GnomAD2 exomes AF: 0.522 AC: 131296 AN: 251356 AF XY: 0.526

Gnomad AFR exome AF: 0.453

Gnomad AMR exome AF: 0.510

Gnomad ASJ exome AF: 0.464

Gnomad EAS exome AF: 0.550

Gnomad FIN exome AF: 0.500

Gnomad NFE exome AF: 0.521

Gnomad OTH exome AF: 0.516

GnomAD4 exome AF: 0.518 AC: 750911 AN: 1449294 Hom.: 196111 Cov.: 31 AF XY: 0.520 AC XY: 375296 AN XY: 721674

African (AFR) AF: 0.451 AC: 14996 AN: 33228

American (AMR) AF: 0.516 AC: 23069 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 11909 AN: 26062

East Asian (EAS) AF: 0.520 AC: 20631 AN: 39658

South Asian (SAS) AF: 0.595 AC: 51163 AN: 85992

European-Finnish (FIN) AF: 0.500 AC: 26709 AN: 53380

Middle Eastern (MID) AF: 0.528 AC: 3025 AN: 5734

European-Non Finnish (NFE) AF: 0.516 AC: 568435 AN: 1100574

Other (OTH) AF: 0.517 AC: 30974 AN: 59960

GnomAD4 genome AF: 0.498 AC: 75618 AN: 151940 Hom.: 19021 Cov.: 32 AF XY: 0.498 AC XY: 36990 AN XY: 74270

African (AFR) AF: 0.452 AC: 18706 AN: 41426

American (AMR) AF: 0.521 AC: 7956 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 1592 AN: 3470

East Asian (EAS) AF: 0.535 AC: 2756 AN: 5156

South Asian (SAS) AF: 0.591 AC: 2841 AN: 4810

European-Finnish (FIN) AF: 0.490 AC: 5179 AN: 10572

Middle Eastern (MID) AF: 0.545 AC: 159 AN: 292

European-Non Finnish (NFE) AF: 0.513 AC: 34862 AN: 67924

Other (OTH) AF: 0.524 AC: 1101 AN: 2102

Alfa AF: 0.512 Hom.: 43159

Bravo AF: 0.499

Asia WGS AF: 0.571 AC: 1987 AN: 3478

EpiCase AF: 0.520

EpiControl AF: 0.524

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Age related macular degeneration 9 (2)
-	-	2	Complement component 3 deficiency (2)
-	-	2	not specified (2)
-	-	1	Atypical hemolytic-uremic syndrome with C3 anomaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.14
DANN	Benign	0.56
PhyloP100		-4.7
PromoterAI		0.0018	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000050
dbscSNV1_RF	Benign	0.0
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: rs2277984; hg19: chr19-6679511; COSMIC: COSV55579365; COSMIC: COSV55579365;