1-196690107-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_000186.4(CFH):c.1204C>T(p.His402Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 1,610,204 control chromosomes in the GnomAD database, including 330,962 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.64 ( 31992 hom., cov: 31)

Exomes 𝑓: 0.64 ( 298970 hom. )

Consequence

CFH
NM_000186.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:13

Conservation

PhyloP100: -8.33

Publications

834 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.2569295E-6).

BP6

Variant 1-196690107-C-T is Benign according to our data. Variant chr1-196690107-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 294490.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4 link	c.1204C>T	p.His402Tyr	missense_variant	Exon 9 of 22	ENST00000367429.9	NP_000177.2
CFH	NM_001014975.3 link	c.1204C>T	p.His402Tyr	missense_variant	Exon 9 of 10		NP_001014975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9 link	c.1204C>T	p.His402Tyr	missense_variant	Exon 9 of 22	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1 link	c.1204C>T	p.His402Tyr	missense_variant	Exon 9 of 27			ENSP00000512341.1

Frequencies

GnomAD3 genomes

AF:

0.645

AC:

97836

AN:

151784

Hom.:

31967

Cov.:

show subpopulations

Gnomad AFR

AF:

0.629

Gnomad AMI

AF:

0.519

Gnomad AMR

AF:

0.737

Gnomad ASJ

AF:

0.661

Gnomad EAS

AF:

0.948

Gnomad SAS

AF:

0.719

Gnomad FIN

AF:

0.563

Gnomad MID

AF:

0.663

Gnomad NFE

AF:

0.618

Gnomad OTH

AF:

0.665

GnomAD2 exomes

AF:

0.680

AC:

169954

AN:

250026

AF XY:

0.673

show subpopulations

Gnomad AFR exome

AF:

0.627

Gnomad AMR exome

AF:

0.834

Gnomad ASJ exome

AF:

0.666

Gnomad EAS exome

AF:

0.954

Gnomad FIN exome

AF:

0.563

Gnomad NFE exome

AF:

0.616

Gnomad OTH exome

AF:

0.660

GnomAD4 exome

AF:

0.636

AC:

927619

AN:

1458302

Hom.:

298970

Cov.:

AF XY:

0.637

AC XY:

462112

AN XY:

725588

show subpopulations

African (AFR)

AF:

0.630

AC:

21019

AN:

33378

American (AMR)

AF:

0.824

AC:

36705

AN:

44562

Ashkenazi Jewish (ASJ)

AF:

0.654

AC:

17060

AN:

26100

East Asian (EAS)

AF:

0.940

AC:

37228

AN:

39602

South Asian (SAS)

AF:

0.694

AC:

59819

AN:

86170

European-Finnish (FIN)

AF:

0.559

AC:

29829

AN:

53332

Middle Eastern (MID)

AF:

0.631

AC:

3633

AN:

5758

European-Non Finnish (NFE)

AF:

0.616

AC:

683562

AN:

1109172

Other (OTH)

AF:

0.644

AC:

38764

AN:

60228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

18087

36174

54260

72347

90434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18510

37020

55530

74040

92550

<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

AF:

0.645

AC:

97903

AN:

151902

Hom.:

31992

Cov.:

AF XY:

0.647

AC XY:

48054

AN XY:

74232

show subpopulations

African (AFR)

AF:

0.629

AC:

26039

AN:

41408

American (AMR)

AF:

0.738

AC:

11238

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.661

AC:

2295

AN:

3470

East Asian (EAS)

AF:

0.949

AC:

4874

AN:

5138

South Asian (SAS)

AF:

0.720

AC:

3470

AN:

4820

European-Finnish (FIN)

AF:

0.563

AC:

5946

AN:

10568

Middle Eastern (MID)

AF:

0.654

AC:

191

AN:

292

European-Non Finnish (NFE)

AF:

0.618

AC:

41974

AN:

67948

Other (OTH)

AF:

0.664

AC:

1404

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1757

3514

5271

7028

8785

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

792

1584

2376

3168

3960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.640

Hom.:

26141

Bravo

AF:

0.660

TwinsUK

AF:

0.612

AC:

2270

ESP6500AA

AF:

0.637

AC:

2808

ESP6500EA

AF:

0.618

AC:

5312

ExAC

AF:

0.671

AC:

81367

Asia WGS

AF:

0.781

AC:

2716

AN:

3478

EpiCase

AF:

0.632

EpiControl

AF:

0.628

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 09, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26895476, 23497844, 28173125, 29686068, 26376595, 15761120, 20038862, 22875704, 19823576, 20869121, 20378180, 20132989, 22277662, 22552255, 16936732, 24036949, 20581873, 23112567, 22933840, 22509112, 20664795, 18604638, 19399715, 22456601, 24550392, 20660596, 21784901, 21930971, 17339482, 20688737, 20574013, 20538999, 20042647, 18263814, 22388616, 21649859, 17464302, 19000922, 17869048, 19187590, 22197220, 20708732, 22965593, 21825189, 18163432, 25087612)

Apr 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Hemolytic uremic syndrome, atypical, susceptibility to, 1

Benign:2

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Age related macular degeneration 4

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Basal laminar drusen

Benign:2

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Factor H deficiency

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Atypical hemolytic-uremic syndrome

Benign:1

Oct 05, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Factor H deficiency;C0730295:Basal laminar drusen;C1853147:Age related macular degeneration 4;C2931788:Atypical hemolytic-uremic syndrome

Benign:1

Oct 02, 2025

Genomenon, Inc, Genomenon, Inc

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

CFH p.His402Tyr (c.1204C>T) is a missense variant that changes the amino acid at residue 402 from Histidine to Tyrosine. This variant is present at high allele frequency in population databases. In conclusion, we classify CFH p.His402Tyr (c.1204C>T) as a benign variant.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.0010

(source)

DANN

Benign

0.22

DEOGEN2

Benign

0.0

.;T;.

Eigen

Benign

-2.8

Eigen_PC

Benign

-2.9

LIST_S2

Benign

0.13

T;T;T

MetaRNN

Benign

0.0000043

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;.;.

PhyloP100

-8.3

PrimateAI

Benign

0.25

PROVEAN

Benign

0.010

N;.;N

Sift

Benign

1.0

T;.;T

Sift4G

Benign

1.0

T;T;T

Vest4

0.087

ClinPred

0.023

GERP RS

-9.1

gMVP

0.58

Mutation Taster

=79/21

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over