1-196747260-C-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_000186.4(CFH):c.3643C>G(p.Arg1215Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic,risk factor (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1215Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CFH
NM_000186.4 missense

Scores

Clinical Significance

Pathogenic; risk factor no assertion criteria provided P:1O:1

Conservation

PhyloP100: 2.27

Publications

25 publications found

Variant links:

Genes affected

CFH (HGNC:4883): (complement factor H) This gene is a member of the Regulator of Complement Activation (RCA) gene cluster and encodes a protein with twenty short consensus repeat (SCR) domains. This protein is secreted into the bloodstream and has an essential role in the regulation of complement activation, restricting this innate defense mechanism to microbial infections. Mutations in this gene have been associated with hemolytic-uremic syndrome (HUS) and chronic hypocomplementemic nephropathy. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Oct 2011]

CFH Gene-Disease associations (from GenCC):

primary membranoproliferative glomerulonephritis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
atypical hemolytic-uremic syndrome
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
hemolytic uremic syndrome, atypical, susceptibility to, 1
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
complement factor H deficiency
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
basal laminar drusen
Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
Doyne honeycomb retinal dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dense deposit disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CFH links:

ENSG00000289697 (HGNC:):

ENSG00000289697 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-196747261-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3376720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 1-196747260-C-G is Pathogenic according to our data. Variant chr1-196747260-C-G is described in ClinVar as Pathogenic|risk_factor. ClinVar VariationId is 16542.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4 link	c.3643C>G	p.Arg1215Gly	missense_variant	Exon 22 of 22	ENST00000367429.9	NP_000177.2	P08603A0A024R962

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9 link	c.3643C>G	p.Arg1215Gly	missense_variant	Exon 22 of 22	1	NM_000186.4	ENSP00000356399.4		P08603
ENSG00000289697	ENST00000696032.1 link	c.3580+63C>G		intron_variant	Intron 22 of 26			ENSP00000512341.1		A0A8Q3SIA1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461720

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111900

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic; risk factor

Submissions summary: Pathogenic:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Atypical hemolytic-uremic syndrome

Pathogenic:1

Oct 25, 2017

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This individual is heterozygous for the c.3643C>G variant in the CFH gene. The c.3643C>G variant has not been reported in any population databases (i.e. gnomAD, ExAC or ESP). This variant has been previously described in the literature and the FH aHUS Mutation Database (http://www.fh-hus.org/fullList.php?protein=FH). In particular, this variant (first reported as R1197G, then R1215G) has been reported in the heterozygous state in multiple affected individuals in a large pedigree, including two individuals with first presentation at 5 months (Edelsten and Tuck 1978 Arch Dis Child 53:255-256; Warwicker et al 1998 Kidney International 53: 836-844; Sansbury et al 2014 Med Genet 51:756-764). The pedigree supported an autosomal dominant mode of inheritance, with incomplete penetrance. In vitro analysis of the p.Arg1215Gly mutant protein showed significant impact on protein function, indicative of loss-of-function (Jozsi et al 2006 J Am Soc Nephrol 17:170-177; Ferreira et al 2009 J Immunol 192:7009-7018). This variant is considered to be pathogenic according to the ACMG guidelines. -

Hemolytic uremic syndrome, atypical, susceptibility to, 1

Other:1

Apr 01, 2003

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.026

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.46

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

-0.18

PhyloP100

2.3

PrimateAI

Benign

0.31

PROVEAN

Pathogenic

-6.0

REVEL

Uncertain

0.50

Sift

Uncertain

0.010

Sift4G

Pathogenic

0.0010

Vest4

0.68

MutPred

0.93

Loss of MoRF binding (P = 0.0247);

MVP

1.0

MPC

2.8

ClinPred

0.98

GERP RS

1.0

gMVP

1.0

Mutation Taster

=40/58

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over