19-861593-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001928.4(CFD):​c.358-106C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000244 in 1,231,342 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 20)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: CFD NM_001928.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.16
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFD	NM_001928.4	c.358-106C>T		intron_variant	Intron 3 of 4	ENST00000327726.11	NP_001919.2
CFD	NM_001317335.2	c.379-106C>T		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>T		intron_variant	Intron 3 of 4	1	NM_001928.4	ENSP00000332139.4

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 0.00000244 AC: 3 AN: 1231342 Hom.: 0 AF XY: 0.00000164 AC XY: 1 AN XY: 610340

African (AFR) AF: 0.00 AC: 0 AN: 28672

American (AMR) AF: 0.00 AC: 0 AN: 34922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23246

East Asian (EAS) AF: 0.00 AC: 0 AN: 34798

South Asian (SAS) AF: 0.00 AC: 0 AN: 74050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3762

European-Non Finnish (NFE) AF: 0.00000317 AC: 3 AN: 945776

Other (OTH) AF: 0.00 AC: 0 AN: 52440

GnomAD4 genome Cov.: 20

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.6
DANN	Benign	0.95
PhyloP100		1.2

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;