19-6694990-G-C

Position:

• chr19-6694990-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000064.4(C3):​c.2951-356C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 151,990 control chromosomes in the GnomAD database, including 18,829 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.48 (18829 hom., cov: 31)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00200

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.559 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C3	NM_000064.4	c.2951-356C>G		intron_variant		ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.2951-356C>G		intron_variant		1	NM_000064.4	ENSP00000245907	P1

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73290 AN: 151870 Hom.: 18829 Cov.: 31

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.570

Gnomad ASJ AF: 0.669

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.487

Gnomad FIN AF: 0.536

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.556

Gnomad OTH AF: 0.538

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.482 AC: 73310 AN: 151990 Hom.: 18829 Cov.: 31 AF XY: 0.483 AC XY: 35910 AN XY: 74292

Gnomad4 AFR AF: 0.297

Gnomad4 AMR AF: 0.569

Gnomad4 ASJ AF: 0.669

Gnomad4 EAS AF: 0.475

Gnomad4 SAS AF: 0.487

Gnomad4 FIN AF: 0.536

Gnomad4 NFE AF: 0.556

Gnomad4 OTH AF: 0.532

Alfa AF: 0.528 Hom.: 11247

Bravo AF: 0.478

Asia WGS AF: 0.457 AC: 1589 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.5
DANN	Benign	0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs10402876; hg19: chr19-6695001;