chr19-863090-AG-A

Variant names:

• chr19-863090-AG-A
• rs34337649
• NM_001928.4:c.617delG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The ENST00000327726.11(CFD):​c.616-1delG variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFD ENST00000327726.11 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.92
• Publications: 4 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_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.7217848 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of 0 (no position change), new splice context is: gccccgtcctgttccggcAGgtg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000327726.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFD	NM_001928.4	MANE Select	c.617delG	p.Gly206fs	frameshift splice_region	Exon 5 of 5	NP_001919.2
	CFD	NM_001317335.2		c.638delG	p.Gly213fs	frameshift splice_region	Exon 5 of 5	NP_001304264.1	K7ERG9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFD	ENST00000327726.11	TSL:1 MANE Select	c.616-1delG		splice_acceptor intron	N/A	ENSP00000332139.4	P00746
	CFD	ENST00000592860.3	TSL:1	c.637-1delG		splice_acceptor intron	N/A	ENSP00000468253.1	K7ERG9
	CFD	ENST00000866187.1		c.616-1delG		splice_acceptor intron	N/A	ENSP00000536246.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1369392 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 672564

African (AFR) AF: 0.00 AC: 0 AN: 31266

American (AMR) AF: 0.00 AC: 0 AN: 35364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24948

East Asian (EAS) AF: 0.00 AC: 0 AN: 35298

South Asian (SAS) AF: 0.00 AC: 0 AN: 78748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4958

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1067796

Other (OTH) AF: 0.00 AC: 0 AN: 57056

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.98		Position offset: 3
DS_AL_spliceai		0.98		Position offset: 2

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

Other links and lift over

dbSNP: rs34337649; hg19: chr19-863090;