rs35186399

Variant names:

• chr19-860766-G-A
• rs35186399
• NM_001928.4:c.205G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:4
• Conservation: PhyloP100: 1.65
• Publications: 13 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1165412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

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.205G>A	p.Glu69Lys	missense	Exon 2 of 5	NP_001919.2
	CFD	NM_001317335.2		c.226G>A	p.Glu76Lys	missense	Exon 2 of 5	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.205G>A	p.Glu69Lys	missense	Exon 2 of 5	ENSP00000332139.4	P00746
	CFD	ENST00000592860.3	TSL:1	c.226G>A	p.Glu76Lys	missense	Exon 2 of 5	ENSP00000468253.1	K7ERG9
	CFD	ENST00000866187.1		c.205G>A	p.Glu69Lys	missense	Exon 2 of 6	ENSP00000536246.1

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

GnomAD2 exomes AF: 0.00538 AC: 923 AN: 171718 AF XY: 0.00545

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 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

African (AFR) AF: 0.00138 AC: 45 AN: 32514

American (AMR) AF: 0.00149 AC: 60 AN: 40158

Ashkenazi Jewish (ASJ) AF: 0.00295 AC: 75 AN: 25426

East Asian (EAS) AF: 0.00 AC: 0 AN: 37650

South Asian (SAS) AF: 0.000267 AC: 22 AN: 82486

European-Finnish (FIN) AF: 0.00857 AC: 305 AN: 35572

Middle Eastern (MID) AF: 0.00186 AC: 8 AN: 4298

European-Non Finnish (NFE) AF: 0.0110 AC: 12016 AN: 1096940

Other (OTH) AF: 0.00592 AC: 348 AN: 58818

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

African (AFR) AF: 0.00210 AC: 87 AN: 41488

American (AMR) AF: 0.00268 AC: 41 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00982 AC: 104 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0101 AC: 687 AN: 67884

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00681 Hom.: 1

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	CFD-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-0.43	N
PhyloP100		1.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.20
Sift	Benign	0.24	T
Sift4G	Benign	0.84	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
Mutation Taster		=94/6	polymorphism

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