rs388862

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.523G>C(p.Glu175Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 959,468 control chromosomes in the GnomAD database, including 50,301 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 0.16 ( 1934 hom., cov: 12)

Exomes 𝑓: 0.13 ( 48367 hom. )

Consequence

CFHR1
NM_002113.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0750

Publications

14 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=0.018653035).

BP6

Variant 1-196828162-G-C is Benign according to our data. Variant chr1-196828162-G-C is described in ClinVar as Benign. ClinVar VariationId is 1241507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 1934 Unknown,AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFHR1	NM_002113.3 link	c.523G>C	p.Glu175Gln	missense_variant	Exon 4 of 6	ENST00000320493.10	NP_002104.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFHR1	ENST00000320493.10 link	c.523G>C	p.Glu175Gln	missense_variant	Exon 4 of 6	1	NM_002113.3	ENSP00000314299.5

Frequencies

GnomAD3 genomes

AF:

0.163

AC:

11828

AN:

72534

Hom.:

1919

Cov.:

show subpopulations

Gnomad AFR

AF:

0.180

Gnomad AMI

AF:

0.0651

Gnomad AMR

AF:

0.215

Gnomad ASJ

AF:

0.196

Gnomad EAS

AF:

0.281

Gnomad SAS

AF:

0.120

Gnomad FIN

AF:

0.146

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.146

Gnomad OTH

AF:

0.170

GnomAD2 exomes

AF:

0.113

AC:

18709

AN:

165808

AF XY:

0.112

show subpopulations

Gnomad AFR exome

AF:

0.169

Gnomad AMR exome

AF:

0.161

Gnomad ASJ exome

AF:

0.214

Gnomad EAS exome

AF:

0.193

Gnomad FIN exome

AF:

0.0566

Gnomad NFE exome

AF:

0.0804

Gnomad OTH exome

AF:

0.113

GnomAD4 exome

AF:

0.129

AC:

114031

AN:

886852

Hom.:

48367

Cov.:

AF XY:

0.132

AC XY:

58826

AN XY:

444486

show subpopulations

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

African (AFR)

AF:

0.244

AC:

3462

AN:

14212

American (AMR)

AF:

0.243

AC:

7322

AN:

30146

Ashkenazi Jewish (ASJ)

AF:

0.243

AC:

3648

AN:

14996

East Asian (EAS)

AF:

0.373

AC:

9075

AN:

24348

South Asian (SAS)

AF:

0.170

AC:

8881

AN:

52354

European-Finnish (FIN)

AF:

0.152

AC:

5737

AN:

37718

Middle Eastern (MID)

AF:

0.103

AC:

345

AN:

3348

European-Non Finnish (NFE)

AF:

0.103

AC:

69582

AN:

673476

Other (OTH)

AF:

0.165

AC:

5979

AN:

36254

⚠️ 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: 0.279

Heterozygous variant carriers

2210

4420

6631

8841

11051

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

890

1780

2670

3560

4450

<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:

0.163

AC:

11862

AN:

72616

Hom.:

1934

Cov.:

AF XY:

0.160

AC XY:

5585

AN XY:

34944

show subpopulations

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

African (AFR)

AF:

0.181

AC:

2496

AN:

13802

American (AMR)

AF:

0.217

AC:

1436

AN:

6630

Ashkenazi Jewish (ASJ)

AF:

0.196

AC:

317

AN:

1614

East Asian (EAS)

AF:

0.282

AC:

695

AN:

2466

South Asian (SAS)

AF:

0.119

AC:

260

AN:

2178

European-Finnish (FIN)

AF:

0.146

AC:

904

AN:

6208

Middle Eastern (MID)

AF:

0.186

AC:

AN:

156

European-Non Finnish (NFE)

AF:

0.146

AC:

5520

AN:

37922

Other (OTH)

AF:

0.172

AC:

158

AN:

918

⚠️ 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: 0.279

Heterozygous variant carriers

734

1467

2201

2934

3668

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<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:

0.431

Hom.:

1645

ExAC

AF:

0.215

AC:

23240

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

0.081

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

8.8

(source)

DANN

Benign

0.55

DEOGEN2

Benign

0.012

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.18

MetaRNN

Benign

0.019

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

-0.075

PROVEAN

Benign

-1.1

REVEL

Benign

0.067

Sift

Benign

0.35

Sift4G

Benign

0.29

Vest4

0.042

ClinPred

0.0040

GERP RS

-3.7

Varity_R

0.11

gMVP

0.57

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