19-860619-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001928.4(CFD):c.58G>A(p.Ala20Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,448,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A20V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: CFD NM_001928.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.89

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16467881).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFD	NM_001928.4	c.58G>A	p.Ala20Thr	missense_variant, splice_region_variant	2/5	ENST00000327726.11
CFD	NM_001317335.2	c.79G>A	p.Ala27Thr	missense_variant, splice_region_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFD	ENST00000327726.11	c.58G>A	p.Ala20Thr	missense_variant, splice_region_variant	2/5	1	NM_001928.4	P2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151946 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000665 AC: 4 AN: 60138 Hom.: 0 AF XY: 0.0000858 AC XY: 3 AN XY: 34960

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000357

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000309 AC: 4 AN: 1296228 Hom.: 0 Cov.: 30 AF XY: 0.00000314 AC XY: 2 AN XY: 636712

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000183

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151946 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74218

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 29, 2022

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 20 of the CFD protein (p.Ala20Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CFD-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.46	T;T
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.72	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.42	N;.
REVEL	Benign	0.084
Sift	Benign	0.39	T;.
Sift4G	Benign	0.56	T;T
Polyphen		0.90	P;.
Vest4		0.11
MutPred		0.39		Gain of relative solvent accessibility (P = 0.0082);.;
MVP		0.85
MPC		0.72
ClinPred		0.091	T
GERP RS		3.5
Varity_R		0.026
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs1374817974; hg19: chr19-860619;