19-861593-C-G

Variant names:

• chr19-861593-C-G
• rs1683563
• NM_001928.4:c.358-106C>G

Variant summary

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

The NM_001928.4(CFD):​c.358-106C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 1,376,048 control chromosomes in the GnomAD database, including 234,286 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 0.50 (19661 hom., cov: 20)
  • Exomes 𝑓: 0.58 (214625 hom.)
• Consequence: CFD NM_001928.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.16
• Publications: 11 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=-0.69).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFD	NM_001928.4	c.358-106C>G		intron_variant	Intron 3 of 4	ENST00000327726.11	NP_001919.2
CFD	NM_001317335.2	c.379-106C>G		intron_variant	Intron 3 of 4		NP_001304264.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFD	ENST00000327726.11	c.358-106C>G		intron_variant	Intron 3 of 4	1	NM_001928.4	ENSP00000332139.4

Frequencies

GnomAD3 genomes AF: 0.501 AC: 73261 AN: 146136 Hom.: 19663 Cov.: 20

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.642

Gnomad AMR AF: 0.475

Gnomad ASJ AF: 0.595

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.550

Gnomad FIN AF: 0.656

Gnomad MID AF: 0.471

Gnomad NFE AF: 0.596

Gnomad OTH AF: 0.493

GnomAD4 exome AF: 0.584 AC: 717651 AN: 1229804 Hom.: 214625 AF XY: 0.584 AC XY: 355743 AN XY: 609578

African (AFR) AF: 0.327 AC: 9358 AN: 28640

American (AMR) AF: 0.446 AC: 15558 AN: 34910

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 13450 AN: 23214

East Asian (EAS) AF: 0.289 AC: 10041 AN: 34788

South Asian (SAS) AF: 0.571 AC: 42260 AN: 74004

European-Finnish (FIN) AF: 0.667 AC: 22451 AN: 33670

Middle Eastern (MID) AF: 0.498 AC: 1873 AN: 3758

European-Non Finnish (NFE) AF: 0.607 AC: 573245 AN: 944418

Other (OTH) AF: 0.561 AC: 29415 AN: 52402

GnomAD4 genome AF: 0.501 AC: 73258 AN: 146244 Hom.: 19661 Cov.: 20 AF XY: 0.500 AC XY: 35550 AN XY: 71060

African (AFR) AF: 0.324 AC: 12755 AN: 39312

American (AMR) AF: 0.475 AC: 6958 AN: 14658

Ashkenazi Jewish (ASJ) AF: 0.595 AC: 2040 AN: 3430

East Asian (EAS) AF: 0.268 AC: 1312 AN: 4892

South Asian (SAS) AF: 0.552 AC: 2452 AN: 4440

European-Finnish (FIN) AF: 0.656 AC: 6454 AN: 9840

Middle Eastern (MID) AF: 0.449 AC: 131 AN: 292

European-Non Finnish (NFE) AF: 0.596 AC: 39625 AN: 66508

Other (OTH) AF: 0.485 AC: 971 AN: 2000

Alfa AF: 0.412 Hom.: 1194

Bravo AF: 0.484

Asia WGS AF: 0.425 AC: 1477 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	4.8
DANN	Benign	0.91
PhyloP100		1.2
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: rs1683563; hg19: chr19-861593;