19-862912-C-T

Variant names:

• chr19-862912-C-T
• rs3826945
• NM_001928.4:c.616-180C>T

Variant summary

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

The NM_001928.4(CFD):​c.616-180C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.711 in 150,240 control chromosomes in the GnomAD database, including 38,690 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 0.71 (38690 hom., cov: 27)
• Consequence: CFD NM_001928.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05
• Publications: 22 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.833 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001928.4. 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.616-180C>T		intron	N/A	NP_001919.2
	CFD	NM_001317335.2		c.637-180C>T		intron	N/A	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.616-180C>T		intron	N/A	ENSP00000332139.4	P00746
	CFD	ENST00000592860.3	TSL:1	c.637-180C>T		intron	N/A	ENSP00000468253.1	K7ERG9
	CFD	ENST00000866187.1		c.616-180C>T		intron	N/A	ENSP00000536246.1

Frequencies

GnomAD3 genomes AF: 0.711 AC: 106745 AN: 150124 Hom.: 38639 Cov.: 27

Gnomad AFR AF: 0.840

Gnomad AMI AF: 0.593

Gnomad AMR AF: 0.611

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.563

Gnomad SAS AF: 0.661

Gnomad FIN AF: 0.663

Gnomad MID AF: 0.694

Gnomad NFE AF: 0.685

Gnomad OTH AF: 0.713

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

GnomAD4 genome AF: 0.711 AC: 106849 AN: 150240 Hom.: 38690 Cov.: 27 AF XY: 0.707 AC XY: 51857 AN XY: 73308

African (AFR) AF: 0.840 AC: 34077 AN: 40564

American (AMR) AF: 0.610 AC: 9263 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 2123 AN: 3462

East Asian (EAS) AF: 0.563 AC: 2845 AN: 5052

South Asian (SAS) AF: 0.661 AC: 3155 AN: 4772

European-Finnish (FIN) AF: 0.663 AC: 6829 AN: 10306

Middle Eastern (MID) AF: 0.705 AC: 206 AN: 292

European-Non Finnish (NFE) AF: 0.685 AC: 46314 AN: 67604

Other (OTH) AF: 0.717 AC: 1499 AN: 2092

Alfa AF: 0.679 Hom.: 12216

Bravo AF: 0.712

Asia WGS AF: 0.607 AC: 2107 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.86
DANN	Benign	0.84
PhyloP100		-1.0
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: rs3826945; hg19: chr19-862912;