rs35186399

chr19-860766-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001928.4(CFD):c.205G>A(p.Glu69Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00886 in 1,565,868 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (11 hom., cov: 31)
  • Exomes 𝑓: 0.0091 (73 hom.)
• Consequence: CFD NM_001928.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.65

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004876882).
• BP6: Variant 19-860766-G-A is Benign according to our data. Variant chr19-860766-G-A is described in ClinVar as [Benign]. Clinvar id is 1165412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-860766-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00659 (1001/152006) while in subpopulation NFE AF= 0.0101 (687/67884). AF 95% confidence interval is 0.00949. There are 11 homozygotes in gnomad4. There are 469 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFD	NM_001928.4	c.205G>A	p.Glu69Lys	missense_variant	2/5	ENST00000327726.11
CFD	NM_001317335.2	c.226G>A	p.Glu76Lys	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFD	ENST00000327726.11	c.205G>A	p.Glu69Lys	missense_variant	2/5	1	NM_001928.4	P2

Frequencies

GnomAD3 genomes AF: 0.00659 AC: 1001 AN: 151890 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.0747

Gnomad AMR AF: 0.00269

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00982

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00538 AC: 923 AN: 171718 Hom.: 6 AF XY: 0.00545 AC XY: 521 AN XY: 95674

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00317

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000193

Gnomad FIN exome AF: 0.00839

Gnomad NFE exome AF: 0.0100

Gnomad OTH exome AF: 0.00817

GnomAD4 exome AF: 0.00911 AC: 12879 AN: 1413862 Hom.: 73 Cov.: 31 AF XY: 0.00876 AC XY: 6143 AN XY: 700986

Gnomad4 AFR exome AF: 0.00138

Gnomad4 AMR exome AF: 0.00149

Gnomad4 ASJ exome AF: 0.00295

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.00857

Gnomad4 NFE exome AF: 0.0110

Gnomad4 OTH exome AF: 0.00592

GnomAD4 genome AF: 0.00659 AC: 1001 AN: 152006 Hom.: 11 Cov.: 31 AF XY: 0.00631 AC XY: 469 AN XY: 74298

Gnomad4 AFR AF: 0.00210

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00982

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00733 Hom.: 0

Bravo AF: 0.00626

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00135 AC: 5

ESP6500EA AF: 0.00756 AC: 56

ExAC AF: 0.00475 AC: 526

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	CFD: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

CFD-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	20
Dann	Benign	0.96
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.40	T;T
MetaRNN	Benign	0.0049	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-0.43	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.96	N;.
REVEL	Benign	0.20
Sift	Benign	0.24	T;.
Sift4G	Benign	0.84	T;T
Polyphen		0.14	B;.
Vest4		0.36
MVP		0.72
MPC		0.34
ClinPred		0.0064	T
GERP RS		2.6
Varity_R		0.49
gMVP		0.66

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: rs35186399; hg19: chr19-860766; COSMIC: COSV99708861; COSMIC: COSV99708861;