rs425757

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002113.3(CFHR1):c.469C>T(p.His157Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,053,124 control chromosomes in the GnomAD database, including 122,751 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 7247 hom., cov: 16)

Exomes 𝑓: 0.30 ( 115504 hom. )

Consequence

CFHR1
NM_002113.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.31

Publications

18 publications found

Variant links:

Genes affected

CFHR1 (HGNC:4888): (complement factor H related 1) This gene encodes a secreted protein belonging to the complement factor H protein family. It binds to Pseudomonas aeruginosa elongation factor Tuf together with plasminogen, which is proteolytically activated. It is proposed that Tuf acts as a virulence factor by acquiring host proteins to the pathogen surface, controlling complement, and facilitating tissue invasion. Mutations in this gene are associated with an increased risk of atypical hemolytic-uremic syndrome. [provided by RefSeq, Oct 2009]

CFHR1 Gene-Disease associations (from GenCC):

dense deposit disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
age related macular degeneration 1
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
hemolytic uremic syndrome, atypical, susceptibility to, 1
Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

CFHR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0069996417).

BP6

Variant 1-196828108-C-T is Benign according to our data. Variant chr1-196828108-C-T is described in ClinVar as Benign. ClinVar VariationId is 1179673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 7247 Unknown,AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFHR1	NM_002113.3 link	c.469C>T	p.His157Tyr	missense_variant	Exon 4 of 6	ENST00000320493.10	NP_002104.2	Q03591

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFHR1	ENST00000320493.10 link	c.469C>T	p.His157Tyr	missense_variant	Exon 4 of 6	1	NM_002113.3	ENSP00000314299.5		Q03591

Frequencies

GnomAD3 genomes

AF:

0.313

AC:

29803

AN:

95098

Hom.:

7230

Cov.:

show subpopulations

Gnomad AFR

AF:

0.349

Gnomad AMI

AF:

0.123

Gnomad AMR

AF:

0.381

Gnomad ASJ

AF:

0.370

Gnomad EAS

AF:

0.464

Gnomad SAS

AF:

0.244

Gnomad FIN

AF:

0.249

Gnomad MID

AF:

0.260

Gnomad NFE

AF:

0.290

Gnomad OTH

AF:

0.314

GnomAD2 exomes

AF:

0.298

AC:

49225

AN:

164932

AF XY:

0.290

show subpopulations

Gnomad AFR exome

AF:

0.449

Gnomad AMR exome

AF:

0.385

Gnomad ASJ exome

AF:

0.387

Gnomad EAS exome

AF:

0.443

Gnomad FIN exome

AF:

0.208

Gnomad NFE exome

AF:

0.243

Gnomad OTH exome

AF:

0.321

GnomAD4 exome

AF:

0.298

AC:

285137

AN:

957956

Hom.:

115504

Cov.:

AF XY:

0.300

AC XY:

143514

AN XY:

479072

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.434

AC:

7544

AN:

17374

American (AMR)

AF:

0.396

AC:

11928

AN:

30158

Ashkenazi Jewish (ASJ)

AF:

0.391

AC:

6680

AN:

17084

East Asian (EAS)

AF:

0.474

AC:

13323

AN:

28096

South Asian (SAS)

AF:

0.319

AC:

18749

AN:

58792

European-Finnish (FIN)

AF:

0.269

AC:

10222

AN:

37968

Middle Eastern (MID)

AF:

0.302

AC:

1138

AN:

3770

European-Non Finnish (NFE)

AF:

0.280

AC:

202773

AN:

724626

Other (OTH)

AF:

0.319

AC:

12780

AN:

40088

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.272

Heterozygous variant carriers

6629

13257

19886

26514

33143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4080

8160

12240

16320

20400

<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:

0.313

AC:

29835

AN:

95168

Hom.:

7247

Cov.:

AF XY:

0.308

AC XY:

14051

AN XY:

45608

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.349

AC:

6446

AN:

18494

American (AMR)

AF:

0.382

AC:

3494

AN:

9142

Ashkenazi Jewish (ASJ)

AF:

0.370

AC:

833

AN:

2254

East Asian (EAS)

AF:

0.465

AC:

1767

AN:

3804

South Asian (SAS)

AF:

0.245

AC:

663

AN:

2708

European-Finnish (FIN)

AF:

0.249

AC:

1876

AN:

7524

Middle Eastern (MID)

AF:

0.253

AC:

AN:

190

European-Non Finnish (NFE)

AF:

0.290

AC:

14233

AN:

49056

Other (OTH)

AF:

0.315

AC:

376

AN:

1192

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.319

Heterozygous variant carriers

897

1793

2690

3586

4483

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

266

532

798

1064

1330

<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:

0.438

Hom.:

2195

ESP6500AA

AF:

0.444

AC:

1612

ESP6500EA

AF:

0.245

AC:

2010

ExAC

AF:

0.328

AC:

36989

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 05, 2018

GeneDx

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

0.084

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.039

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.0019

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0056

LIST_S2

Benign

0.17

MetaRNN

Benign

0.0070

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.45

PhyloP100

-2.3

PROVEAN

Benign

-0.39

REVEL

Benign

0.036

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.14

Vest4

0.041

MPC

1.0

ClinPred

0.0066

GERP RS

-4.3

Varity_R

0.039

gMVP

0.38

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