rs121913051

Positions:

• chr1-196747260-C-G
• chr1-196747260-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong PP5

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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. 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
• Clinical Significance: Pathogenic; risk factor no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 2.27

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PS1: Transcript NM_000186.4 (CFH) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a domain Sushi 20 (size 60) in uniprot entity CFAH_HUMAN there are 17 pathogenic changes around while only 1 benign (94%) in NM_000186.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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 id is 16542.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-196747260-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFH	NM_000186.4	c.3643C>G	p.Arg1215Gly	missense_variant	22/22	ENST00000367429.9	NP_000177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.3643C>G	p.Arg1215Gly	missense_variant	22/22	1	NM_000186.4	ENSP00000356399	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461720 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727172

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic; risk factor

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Atypical hemolytic-uremic syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Oct 25, 2017

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

risk factor, no assertion criteria provided

literature only

OMIM

Apr 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	22
DANN	Uncertain	0.98
Eigen	Benign	-0.026
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.46	T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	-0.18	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.68
MutPred		0.93		Loss of MoRF binding (P = 0.0247);
MVP		1.0
MPC		2.8
ClinPred		0.98	D
GERP RS		1.0
gMVP		1.0

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: rs121913051; hg19: chr1-196716390;