rs121913055

Variant names:

• chr1-196747183-T-G
• rs121913055
• NM_000186.4:c.3566T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000186.4(CFH):​c.3566T>G​(p.Leu1189Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1189F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFH NM_000186.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 1.55
• Publications: 10 publications found

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):

• C3 glomerulonephritis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• atypical hemolytic-uremic syndrome

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• basal laminar drusen

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hemolytic uremic syndrome, atypical, susceptibility to, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• complement factor H deficiency

  Inheritance: AR Classification: STRONG, MODERATE 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

ENSG00000289697 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 20 uncertain 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 chr1-196747182-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1693716.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000186.4. 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
	CFH	NM_000186.4	MANE Select	c.3566T>G	p.Leu1189Arg	missense	Exon 22 of 22	NP_000177.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	ENST00000367429.9	TSL:1 MANE Select	c.3566T>G	p.Leu1189Arg	missense	Exon 22 of 22	ENSP00000356399.4	P08603
	ENSG00000289697	ENST00000696032.1		c.3566T>G	p.Leu1189Arg	missense	Exon 22 of 27	ENSP00000512341.1	A0A8Q3SIA1
	CFH	ENST00000466229.5	TSL:1	n.6664T>G		non_coding_transcript_exon	Exon 16 of 16

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Atypical hemolytic-uremic syndrome (1)
-	-	-	Hemolytic uremic syndrome, atypical, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	15
DANN	Uncertain	0.99
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.45	T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.82	T
PhyloP100		1.5
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.061	T
Vest4		0.68
MutPred		0.79		Gain of MoRF binding (P = 0.0229)
MVP		0.96
MPC		2.2
ClinPred		0.83	D
GERP RS		1.9
gMVP		0.99
Mutation Taster		=27/73	disease causing

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: rs121913055; hg19: chr1-196716313;