19-860620-C-T

Position:

• chr19-860620-C-T

Variant summary

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

The NM_001928.4(CFD):​c.59C>T​(p.Ala20Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,296,912 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CFD NM_001928.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.683

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=0.14711913).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFD	NM_001928.4	c.59C>T	p.Ala20Val	missense_variant	2/5	ENST00000327726.11	NP_001919.2
CFD	NM_001317335.2	c.80C>T	p.Ala27Val	missense_variant	2/5		NP_001304264.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFD	ENST00000327726.11	c.59C>T	p.Ala20Val	missense_variant	2/5	1	NM_001928.4	ENSP00000332139	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000108 AC: 14 AN: 1296912 Hom.: 0 Cov.: 30 AF XY: 0.0000141 AC XY: 9 AN XY: 637074

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: 0.0000147

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000115

Gnomad4 OTH exome AF: 0.0000186

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000186 AC: 1

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2021

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. 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"). This variant has not been reported in the literature in individuals with CFD-related conditions. While this variant is present in population databases (rs755875279), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces alanine with valine at codon 20 of the CFD protein (p.Ala20Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.00068	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.44	T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.52	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.69	N;.
REVEL	Benign	0.066
Sift	Benign	0.28	T;.
Sift4G	Benign	0.38	T;T
Polyphen		0.82	P;.
Vest4		0.17
MutPred		0.44		Gain of loop (P = 0.0079);.;
MVP		0.87
MPC		0.69
ClinPred		0.14	T
GERP RS		3.5
Varity_R		0.063
gMVP		0.45

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: rs755875279; hg19: chr19-860620;