rs1683564

Variant names:

• chr19-859214-C-A
• rs1683564
• ENST00000695942.1:c.-381C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000695942.1(CFD):​c.-381C>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 152,070 control chromosomes in the GnomAD database, including 7,987 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 0.31 (7987 hom., cov: 33)
• Consequence: CFD ENST00000695942.1 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.673
• Publications: 27 publications found

Genes affected

CFD (HGNC:2771): (complement factor D) This gene encodes a member of the S1, or chymotrypsin, family of serine peptidases. This protease catalyzes the cleavage of factor B, the rate-limiting step of the alternative pathway of complement activation. This protein also functions as an adipokine, a cell signaling protein secreted by adipocytes, which regulates insulin secretion in mice. Mutations in this gene underlie complement factor D deficiency, which is associated with recurrent bacterial meningitis infections in human patients. Alternative splicing of this gene results in multiple transcript variants. At least one of these variants encodes a preproprotein that is proteolytically processed to generate the mature protease. [provided by RefSeq, Nov 2015]

CFD Gene-Disease associations (from GenCC):

• recurrent Neisseria infections due to factor D deficiency

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFD	ENST00000695942.1	c.-381C>A		upstream_gene_variant				ENSP00000512275.1
CFD	ENST00000695943.1	c.-365C>A		upstream_gene_variant				ENSP00000512276.1

Frequencies

GnomAD3 genomes AF: 0.315 AC: 47801 AN: 151952 Hom.: 7988 Cov.: 33

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.374

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.318

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

GnomAD4 genome AF: 0.314 AC: 47798 AN: 152070 Hom.: 7987 Cov.: 33 AF XY: 0.318 AC XY: 23674 AN XY: 74342

African (AFR) AF: 0.189 AC: 7857 AN: 41476

American (AMR) AF: 0.406 AC: 6201 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 1264 AN: 3472

East Asian (EAS) AF: 0.295 AC: 1527 AN: 5176

South Asian (SAS) AF: 0.405 AC: 1956 AN: 4824

European-Finnish (FIN) AF: 0.374 AC: 3953 AN: 10572

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.351 AC: 23834 AN: 67964

Other (OTH) AF: 0.315 AC: 664 AN: 2110

Alfa AF: 0.342 Hom.: 15249

Bravo AF: 0.311

Asia WGS AF: 0.359 AC: 1253 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.5
DANN	Benign	0.54
PhyloP100		-0.67
PromoterAI		-0.019	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1683564; hg19: chr19-859214;