rs35186399

Positions:

chr19-860766-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.65

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFD	NM_001928.4 linkuse as main transcript	c.205G>A	p.Glu69Lys	missense_variant	2/5	ENST00000327726.11	NP_001919.2	P00746
CFD	NM_001317335.2 linkuse as main transcript	c.226G>A	p.Glu76Lys	missense_variant	2/5		NP_001304264.1	P00746K7ERG9A6XNE2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFD	ENST00000327726.11 linkuse as main transcript	c.205G>A	p.Glu69Lys	missense_variant	2/5	1	NM_001928.4	ENSP00000332139.4		P00746

Frequencies

GnomAD3 genomes

AF:

0.00659

AC:

1001

AN:

151890

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00545

AC XY:

521

AN XY:

95674

show subpopulations

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.:

Cov.:

AF XY:

0.00876

AC XY:

6143

AN XY:

700986

show subpopulations

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.:

Cov.:

AF XY:

0.00631

AC XY:

469

AN XY:

74298

show subpopulations

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.:

Bravo

AF:

0.00626

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00135

AC:

ESP6500EA

AF:

0.00756

AC:

ExAC

AF:

0.00475

AC:

526

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	CFD: BS1, BS2 -

CFD-related disorder

Benign:1

Benign, no assertion criteria provided

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

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.32

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.40

T;T

MetaRNN

Benign

0.0049

T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

-0.43

N;.

PrimateAI

Uncertain

0.54

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over