19-6686648-T-C

Variant names:

• chr19-6686648-T-C
• rs237554
• NM_000064.4:c.3646+98A>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.3646+98A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 1,299,660 control chromosomes in the GnomAD database, including 494,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (58228 hom., cov: 31)
  • Exomes 𝑓: 0.87 (436220 hom.)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.280
• Publications: 20 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=-0.89).
• BP6: Variant 19-6686648-T-C is Benign according to our data. Variant chr19-6686648-T-C is described in ClinVar as Benign. ClinVar VariationId is 1192670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.965 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4	c.3646+98A>G		intron_variant	Intron 28 of 40	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.3646+98A>G		intron_variant	Intron 28 of 40	1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.874 AC: 132945 AN: 152058 Hom.: 58196 Cov.: 31

Gnomad AFR AF: 0.886

Gnomad AMI AF: 0.889

Gnomad AMR AF: 0.894

Gnomad ASJ AF: 0.872

Gnomad EAS AF: 0.988

Gnomad SAS AF: 0.863

Gnomad FIN AF: 0.859

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.857

Gnomad OTH AF: 0.877

GnomAD4 exome AF: 0.871 AC: 999587 AN: 1147484 Hom.: 436220 Cov.: 16 AF XY: 0.869 AC XY: 509024 AN XY: 585520

African (AFR) AF: 0.888 AC: 24605 AN: 27720

American (AMR) AF: 0.931 AC: 41246 AN: 44310

Ashkenazi Jewish (ASJ) AF: 0.854 AC: 20719 AN: 24254

East Asian (EAS) AF: 0.984 AC: 37720 AN: 38350

South Asian (SAS) AF: 0.860 AC: 68495 AN: 79620

European-Finnish (FIN) AF: 0.858 AC: 34996 AN: 40802

Middle Eastern (MID) AF: 0.858 AC: 3061 AN: 3568

European-Non Finnish (NFE) AF: 0.864 AC: 724659 AN: 838524

Other (OTH) AF: 0.876 AC: 44086 AN: 50336

GnomAD4 genome AF: 0.874 AC: 133031 AN: 152176 Hom.: 58228 Cov.: 31 AF XY: 0.875 AC XY: 65074 AN XY: 74412

African (AFR) AF: 0.886 AC: 36766 AN: 41504

American (AMR) AF: 0.894 AC: 13669 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.872 AC: 3026 AN: 3472

East Asian (EAS) AF: 0.988 AC: 5122 AN: 5186

South Asian (SAS) AF: 0.861 AC: 4152 AN: 4820

European-Finnish (FIN) AF: 0.859 AC: 9109 AN: 10604

Middle Eastern (MID) AF: 0.813 AC: 239 AN: 294

European-Non Finnish (NFE) AF: 0.857 AC: 58293 AN: 67986

Other (OTH) AF: 0.874 AC: 1846 AN: 2112

Alfa AF: 0.866 Hom.: 82567

Bravo AF: 0.881

Asia WGS AF: 0.907 AC: 3154 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Age related macular degeneration 9 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Complement component 3 deficiency Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.7
DANN	Benign	0.75
PhyloP100		-0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs237554; hg19: chr19-6686659;