1-196690107-C-G

Variant names:

• chr1-196690107-C-G
• rs1061170
• NM_000186.4:c.1204C>G
• CFH p.His402Asp

GermlineCancer (beta)

Variant summary

Our verdict is

Uncertain significance

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received 0 classification points (ACMG Germline Pathogenicity v2019): 2P and 2B. PM2BP4_Moderate

The NM_000186.4(CFH):c.1204C>G (p.His402Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.H402Y: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 294490)

• Frequency: Genomes: not found (cov: 31)
• Consequence: CFH NM_000186.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -8.33
• Publications: 847 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
• 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:):

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Uncertain_significance. The variant received 0 points.

• PM2: Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.000137 by highest known P/LP ClinVar AF 0.000137) — PM2 moderate.
• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000186.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	NM_000186.4	MANE Select	c.1204C>G	p.His402Asp	missense	Exon 9 of 22	NP_000177.2
	CFH	NM_001014975.3		c.1204C>G	p.His402Asp	missense	Exon 9 of 10	NP_001014975.1	A0A0D9SG88

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	ENST00000367429.9	TSL:1 MANE Select	c.1204C>G	p.His402Asp	missense	Exon 9 of 22	ENSP00000356399.4	P08603
	ENSG00000289697	ENST00000696032.1		c.1204C>G	p.His402Asp	missense	Exon 9 of 27	ENSP00000512341.1	A0A8Q3SIA1
	CFH	ENST00000630130.2	TSL:1	c.1204C>G	p.His402Asp	missense	Exon 9 of 10	ENSP00000487250.1	A0A0D9SG88

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 50

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Factor H deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.0010
DANN	Benign	0.50
DEOGEN2	Benign	0.028	T
Eigen	Benign	-2.6
Eigen_PC	Benign	-2.8
FATHMM_MKL	Benign	0.0047	N
LIST_S2	Benign	0.11	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
PhyloP100		-8.3
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.10
Sift	Benign	0.48	T
Sift4G	Benign	0.20	T
gMVP		0.69
Mutation Taster		=51/49	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1061170;

hg19: chr1-196659237;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar