1-196677613-G-T

Variant names:

• chr1-196677613-G-T
• rs121913054
• NM_000186.4:c.565G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000186.4(CFH):​c.565G>T​(p.Glu189*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,406 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 (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CFH NM_000186.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.94
• Publications: 4 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):

• 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

ENSG00000289697 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-196677613-G-T is Pathogenic according to our data. Variant chr1-196677613-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 16547.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	c.565G>T	p.Glu189*	stop_gained	Exon 5 of 22	ENST00000367429.9	NP_000177.2
CFH	NM_001014975.3	c.565G>T	p.Glu189*	stop_gained	Exon 5 of 10		NP_001014975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.565G>T	p.Glu189*	stop_gained	Exon 5 of 22	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.565G>T	p.Glu189*	stop_gained	Exon 5 of 27			ENSP00000512341.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460406 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726584

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110802

Other (OTH) AF: 0.00 AC: 0 AN: 60328

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000912 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Factor H deficiency Pathogenic:2

Oct 02, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

CFH p.Glu189Ter (c.565G>T) is a nonsense variant that introduces a premature stop codon at amino acid position 189, creating a truncated protein that is predicted to undergo nonsense-mediated mRNA decay. This variant has been observed in at least one proband affected with complement factor H deficiency (PMID:10803850). The variant was found to segregate with disease in at least one affected family (PMID:10803850). It is absent or not present at a significant frequency in gnomAD. In conclusion, we classify CFH p.Glu189Ter (c.565G>T) as a pathogenic variant.

Apr 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.079
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.0	.;.
MetaRNN	Benign	0.0	.;.
MutationAssessor	Benign	0.0	.;.
PhyloP100		1.9
PROVEAN	Benign	0.0	.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.
Sift4G	Pathogenic	0.0	.;.
Vest4		0.82
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121913054; hg19: chr1-196646743; COSMIC: COSV62777006; COSMIC: COSV62777006;