rs800292

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000186.4(CFH):c.184G>A(p.Val62Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 1,612,358 control chromosomes in the GnomAD database, including 70,983 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 15198 hom., cov: 31)

Exomes 𝑓: 0.26 ( 55785 hom. )

Consequence

CFH
NM_000186.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13O:2

Conservation

PhyloP100: 1.60

Publications

490 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.604542E-6).

BP6

Variant 1-196673103-G-A is Benign according to our data. Variant chr1-196673103-G-A is described in ClinVar as Benign. ClinVar VariationId is 16550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4 link	c.184G>A	p.Val62Ile	missense_variant	Exon 2 of 22	ENST00000367429.9	NP_000177.2
CFH	NM_001014975.3 link	c.184G>A	p.Val62Ile	missense_variant	Exon 2 of 10		NP_001014975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9 link	c.184G>A	p.Val62Ile	missense_variant	Exon 2 of 22	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1 link	c.184G>A	p.Val62Ile	missense_variant	Exon 2 of 27			ENSP00000512341.1

Frequencies

GnomAD3 genomes

AF:

0.397

AC:

60251

AN:

151828

Hom.:

15151

Cov.:

show subpopulations

Gnomad AFR

AF:

0.716

Gnomad AMI

AF:

0.294

Gnomad AMR

AF:

0.388

Gnomad ASJ

AF:

0.270

Gnomad EAS

AF:

0.423

Gnomad SAS

AF:

0.326

Gnomad FIN

AF:

0.296

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.234

Gnomad OTH

AF:

0.357

GnomAD2 exomes

AF:

0.317

AC:

79518

AN:

250544

AF XY:

0.305

show subpopulations

Gnomad AFR exome

AF:

0.725

Gnomad AMR exome

AF:

0.375

Gnomad ASJ exome

AF:

0.269

Gnomad EAS exome

AF:

0.421

Gnomad FIN exome

AF:

0.302

Gnomad NFE exome

AF:

0.235

Gnomad OTH exome

AF:

0.271

GnomAD4 exome

AF:

0.261

AC:

381288

AN:

1460412

Hom.:

55785

Cov.:

AF XY:

0.261

AC XY:

189294

AN XY:

726594

show subpopulations

African (AFR)

AF:

0.734

AC:

24551

AN:

33446

American (AMR)

AF:

0.381

AC:

17038

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.264

AC:

6898

AN:

26126

East Asian (EAS)

AF:

0.415

AC:

16441

AN:

39658

South Asian (SAS)

AF:

0.314

AC:

27066

AN:

86224

European-Finnish (FIN)

AF:

0.296

AC:

15784

AN:

53400

Middle Eastern (MID)

AF:

0.205

AC:

1181

AN:

5760

European-Non Finnish (NFE)

AF:

0.230

AC:

255332

AN:

1110734

Other (OTH)

AF:

0.282

AC:

16997

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

14374

28748

43122

57496

71870

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9126

18252

27378

36504

45630

<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:

0.397

AC:

60366

AN:

151946

Hom.:

15198

Cov.:

AF XY:

0.399

AC XY:

29600

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.716

AC:

29665

AN:

41424

American (AMR)

AF:

0.389

AC:

5937

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.270

AC:

936

AN:

3464

East Asian (EAS)

AF:

0.423

AC:

2173

AN:

5136

South Asian (SAS)

AF:

0.326

AC:

1571

AN:

4814

European-Finnish (FIN)

AF:

0.296

AC:

3130

AN:

10572

Middle Eastern (MID)

AF:

0.156

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.234

AC:

15888

AN:

67956

Other (OTH)

AF:

0.357

AC:

752

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1508

3016

4524

6032

7540

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

522

1044

1566

2088

2610

<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:

0.279

Hom.:

34897

Bravo

AF:

0.417

TwinsUK

AF:

0.234

AC:

866

ALSPAC

AF:

0.226

AC:

872

ESP6500AA

AF:

0.708

AC:

3119

ESP6500EA

AF:

0.222

AC:

1909

ExAC

AF:

0.320

AC:

38882

Asia WGS

AF:

0.432

AC:

1502

AN:

3478

EpiCase

AF:

0.227

EpiControl

AF:

0.231

ClinVar

Significance: Benign

Submissions summary: Benign:13Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21106043, 25087612, 20538655, 23274582, 18340363, 19549636, 18421087, 20574013, 24722444, 21270465, 24550392, 22509112, 23441108, 20132989, 19187823, 21397333, 21555552, 16299065, 29686068, 28173125) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Department of Ophthalmology and Visual Sciences Kyoto University

Significance:not provided

Review Status:no classification provided

Collection Method:not provided

- -

Basal laminar drusen

Benign:3

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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:2Other:1

Sep 11, 2011

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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). 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. -

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

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

Focal segmental glomerulosclerosis

Benign:1

Sep 27, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.087

DEOGEN2

Benign

0.0040

.;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0021

LIST_S2

Benign

0.36

T;T;T

MetaRNN

Benign

0.0000056

T;T;T

MetaSVM

Benign

-0.94

PhyloP100

1.6

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.49

N;.;N

REVEL

Benign

0.14

Sift

Benign

1.0

T;.;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.10

MPC

0.11

ClinPred

0.0013

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.69

Mutation Taster

=75/25

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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