1-196737547-G-T

Variant names:

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.2669G>T(p.Ser890Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,613,318 control chromosomes in the GnomAD database, including 1,602 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S890T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.059 ( 844 hom., cov: 32)

Exomes 𝑓: 0.0070 ( 758 hom. )

Consequence

CFH
NM_000186.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -3.46

Publications

27 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):

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

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=0.0057353973).

BP6

Variant 1-196737547-G-T is Benign according to our data. Variant chr1-196737547-G-T is described in ClinVar as Benign. ClinVar VariationId is 294507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

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.2669G>T	p.Ser890Ile	missense	Exon 17 of 22	NP_000177.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CFH	ENST00000367429.9	TSL:1 MANE Select	c.2669G>T	p.Ser890Ile	missense	Exon 17 of 22	ENSP00000356399.4	P08603
ENSG00000289697	ENST00000696032.1		c.2669G>T	p.Ser890Ile	missense	Exon 17 of 27	ENSP00000512341.1	A0A8Q3SIA1
CFH	ENST00000466229.5	TSL:1	n.4685G>T		non_coding_transcript_exon	Exon 12 of 16

Frequencies

GnomAD3 genomes

AF:

0.0586

AC:

8906

AN:

152054

Hom.:

841

Cov.:

show subpopulations

Gnomad AFR

AF:

0.199

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0255

Gnomad ASJ

AF:

0.0288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00148

Gnomad OTH

AF:

0.0450

GnomAD2 exomes

AF:

0.0170

AC:

4258

AN:

251058

AF XY:

0.0129

show subpopulations

Gnomad AFR exome

AF:

0.205

Gnomad AMR exome

AF:

0.0111

Gnomad ASJ exome

AF:

0.0285

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00148

Gnomad OTH exome

AF:

0.00980

GnomAD4 exome

AF:

0.00703

AC:

10265

AN:

1461146

Hom.:

758

Cov.:

AF XY:

0.00631

AC XY:

4588

AN XY:

726892

show subpopulations

African (AFR)

AF:

0.203

AC:

6779

AN:

33434

American (AMR)

AF:

0.0124

AC:

554

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0288

AC:

752

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39564

South Asian (SAS)

AF:

0.00160

AC:

138

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.0172

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000793

AC:

882

AN:

1111570

Other (OTH)

AF:

0.0176

AC:

1061

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

425

851

1276

1702

2127

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

220

440

660

880

1100

<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:

0.0587

AC:

8936

AN:

152172

Hom.:

844

Cov.:

AF XY:

0.0569

AC XY:

4237

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.199

AC:

8246

AN:

41490

American (AMR)

AF:

0.0254

AC:

388

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0288

AC:

100

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00149

AC:

101

AN:

68008

Other (OTH)

AF:

0.0445

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

370

740

1109

1479

1849

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<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:

0.0230

Hom.:

986

Bravo

AF:

0.0667

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.189

AC:

834

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.0198

AC:

2400

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.00224

EpiControl

AF:

0.00267

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Age related macular degeneration 4 (2)

Basal laminar drusen (2)

Hemolytic uremic syndrome, atypical, susceptibility to, 1 (2)

Atypical hemolytic-uremic syndrome (1)

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II (1)

Factor H deficiency (1)

Factor H deficiency;C0730295:Basal laminar drusen;C1853147:Age related macular degeneration 4;C2931788:Atypical hemolytic-uremic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.081

(source)

DANN

Benign

0.94

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0070

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0057

MetaSVM

Benign

-1.1

PhyloP100

-3.5

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.71

REVEL

Benign

0.057

Sift

Benign

0.16

Sift4G

Benign

0.14

Vest4

0.024

MPC

0.17

ClinPred

0.0013

GERP RS

-3.6

gMVP

0.72

Mutation Taster

=81/19

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over