19-863116-T-G

Variant names:

• chr19-863116-T-G
• NM_001928.4:c.640T>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001928.4(CFD):​c.640T>G​(p.Cys214Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000726 in 1,377,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: CFD NM_001928.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.69

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFD	NM_001928.4	c.640T>G	p.Cys214Gly	missense_variant	Exon 5 of 5	ENST00000327726.11	NP_001919.2
CFD	NM_001317335.2	c.661T>G	p.Cys221Gly	missense_variant	Exon 5 of 5		NP_001304264.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFD	ENST00000327726.11	c.640T>G	p.Cys214Gly	missense_variant	Exon 5 of 5	1	NM_001928.4	ENSP00000332139.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.26e-7 AC: 1 AN: 1377902 Hom.: 0 Cov.: 32 AF XY: 0.00000147 AC XY: 1 AN XY: 678736

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.31e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.81	T;T
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.0089	D
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-8.8	D;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.025	D;.
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.62
MutPred		0.81		Gain of disorder (P = 0.0138);.;
MVP		0.95
MPC		1.0
ClinPred		0.97	D
GERP RS		4.3
Varity_R		0.97
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-863116;