rs551397

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.59-36C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 1,542,258 control chromosomes in the GnomAD database, including 67,908 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 15261 hom., cov: 32)

Exomes 𝑓: 0.26 ( 52647 hom. )

Consequence

CFH
NM_000186.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.145

Publications

19 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 (BayesDel_noAF=-0.97).

BP6

Variant 1-196672942-C-T is Benign according to our data. Variant chr1-196672942-C-T is described in ClinVar as Benign. ClinVar VariationId is 1209735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4 link	c.59-36C>T		intron_variant	Intron 1 of 21	ENST00000367429.9	NP_000177.2	P08603A0A024R962
CFH	NM_001014975.3 link	c.59-36C>T		intron_variant	Intron 1 of 9		NP_001014975.1	A0A0D9SG88

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9 link	c.59-36C>T		intron_variant	Intron 1 of 21	1	NM_000186.4	ENSP00000356399.4		P08603
ENSG00000289697	ENST00000696032.1 link	c.59-36C>T		intron_variant	Intron 1 of 26			ENSP00000512341.1		A0A8Q3SIA1

Frequencies

GnomAD3 genomes

AF:

0.398

AC:

60359

AN:

151790

Hom.:

15215

Cov.:

show subpopulations

Gnomad AFR

AF:

0.718

Gnomad AMI

AF:

0.292

Gnomad AMR

AF:

0.389

Gnomad ASJ

AF:

0.270

Gnomad EAS

AF:

0.424

Gnomad SAS

AF:

0.327

Gnomad FIN

AF:

0.297

Gnomad MID

AF:

0.153

Gnomad NFE

AF:

0.234

Gnomad OTH

AF:

0.357

GnomAD2 exomes

AF:

0.313

AC:

74917

AN:

239220

AF XY:

0.303

show subpopulations

Gnomad AFR exome

AF:

0.725

Gnomad AMR exome

AF:

0.372

Gnomad ASJ exome

AF:

0.266

Gnomad EAS exome

AF:

0.417

Gnomad FIN exome

AF:

0.300

Gnomad NFE exome

AF:

0.231

Gnomad OTH exome

AF:

0.268

GnomAD4 exome

AF:

0.260

AC:

360929

AN:

1390350

Hom.:

52647

Cov.:

AF XY:

0.259

AC XY:

180272

AN XY:

695552

show subpopulations

African (AFR)

AF:

0.733

AC:

22951

AN:

31300

American (AMR)

AF:

0.379

AC:

16572

AN:

43730

Ashkenazi Jewish (ASJ)

AF:

0.263

AC:

6731

AN:

25590

East Asian (EAS)

AF:

0.414

AC:

16104

AN:

38936

South Asian (SAS)

AF:

0.313

AC:

26268

AN:

83992

European-Finnish (FIN)

AF:

0.295

AC:

15652

AN:

53064

Middle Eastern (MID)

AF:

0.205

AC:

1154

AN:

5632

European-Non Finnish (NFE)

AF:

0.228

AC:

239215

AN:

1050242

Other (OTH)

AF:

0.281

AC:

16282

AN:

57864

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

11908

23816

35725

47633

59541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8390

16780

25170

33560

41950

<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:

0.398

AC:

60471

AN:

151908

Hom.:

15261

Cov.:

AF XY:

0.399

AC XY:

29656

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.718

AC:

29753

AN:

41452

American (AMR)

AF:

0.389

AC:

5945

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.270

AC:

936

AN:

3468

East Asian (EAS)

AF:

0.424

AC:

2185

AN:

5152

South Asian (SAS)

AF:

0.328

AC:

1578

AN:

4818

European-Finnish (FIN)

AF:

0.297

AC:

3124

AN:

10512

Middle Eastern (MID)

AF:

0.158

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.234

AC:

15883

AN:

67926

Other (OTH)

AF:

0.357

AC:

755

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1532

3065

4597

6130

7662

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:

0.295

Hom.:

7100

Bravo

AF:

0.418

Asia WGS

AF:

0.433

AC:

1504

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 10, 2021

GeneDx

Significance:Benign

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

- -

Factor H deficiency

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hemolytic uremic syndrome, atypical, susceptibility to, 1

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Age related macular degeneration 4

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Basal laminar drusen

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.84

(source)

DANN

Benign

0.14

PhyloP100

-0.14

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over