rs35662416

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_030787.4(CFHR5):c.1067G>A(p.Arg356His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0237 in 1,609,466 control chromosomes in the GnomAD database, including 548 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R356C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.017 ( 29 hom., cov: 32)

Exomes 𝑓: 0.024 ( 519 hom. )

Consequence

CFHR5
NM_030787.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -2.28

Publications

23 publications found

Variant links:

Genes affected

CFHR5 (HGNC:24668): (complement factor H related 5) This gene is a member of a small complement factor H (CFH) gene cluster on chromosome 1. Each member of this gene family contains multiple short consensus repeats (SCRs) typical of regulators of complement activation. The protein encoded by this gene has nine SCRs with the first two repeats having heparin binding properties, a region within repeats 5-7 having heparin binding and C reactive protein binding properties, and the C-terminal repeats being similar to a complement component 3 b (C3b) binding domain. This protein co-localizes with C3, binds C3b in a dose-dependent manner, and is recruited to tissues damaged by C-reactive protein. Allelic variations in this gene have been associated, but not causally linked, with two different forms of kidney disease: membranoproliferative glomerulonephritis type II (MPGNII) and hemolytic uraemic syndrome (HUS). [provided by RefSeq, Jan 2010]

CFHR5 Gene-Disease associations (from GenCC):

C3 glomerulonephritis
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

CFHR5 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=0.009272099).

BP6

Variant 1-196998224-G-A is Benign according to our data. Variant chr1-196998224-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 402533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0171 (2602/152062) while in subpopulation NFE AF = 0.0261 (1773/67952). AF 95% confidence interval is 0.0251. There are 29 homozygotes in GnomAd4. There are 1180 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2602 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030787.4. 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
	CFHR5	NM_030787.4	MANE Select	c.1067G>A	p.Arg356His	missense	Exon 7 of 10	NP_110414.1	Q9BXR6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CFHR5	ENST00000256785.5	TSL:1 MANE Select	c.1067G>A	p.Arg356His	missense	Exon 7 of 10	ENSP00000256785.4	Q9BXR6
CFHR5	ENST00000699466.1		c.812G>A	p.Arg271His	missense	Exon 7 of 10	ENSP00000514393.1	A0A8V8TNA3
CFHR5	ENST00000699468.1		c.161G>A	p.Arg54His	missense	Exon 3 of 6	ENSP00000514394.1	A0A8V8TNF4

Frequencies

GnomAD3 genomes

AF:

0.0171

AC:

2603

AN:

151944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00547

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0250

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.0121

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0261

Gnomad OTH

AF:

0.0230

GnomAD2 exomes

AF:

0.0163

AC:

4073

AN:

249494

AF XY:

0.0165

show subpopulations

Gnomad AFR exome

AF:

0.00522

Gnomad AMR exome

AF:

0.0191

Gnomad ASJ exome

AF:

0.00568

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0130

Gnomad NFE exome

AF:

0.0246

Gnomad OTH exome

AF:

0.0228

GnomAD4 exome

AF:

0.0244

AC:

35503

AN:

1457404

Hom.:

519

Cov.:

AF XY:

0.0238

AC XY:

17233

AN XY:

725058

show subpopulations

African (AFR)

AF:

0.00405

AC:

135

AN:

33362

American (AMR)

AF:

0.0192

AC:

856

AN:

44520

Ashkenazi Jewish (ASJ)

AF:

0.00484

AC:

126

AN:

26042

East Asian (EAS)

AF:

0.00

AC:

AN:

39502

South Asian (SAS)

AF:

0.00340

AC:

291

AN:

85594

European-Finnish (FIN)

AF:

0.0150

AC:

800

AN:

53218

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0286

AC:

31761

AN:

1109284

Other (OTH)

AF:

0.0245

AC:

1473

AN:

60136

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

1534

3069

4603

6138

7672

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1200

2400

3600

4800

6000

<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:

0.0171

AC:

2602

AN:

152062

Hom.:

Cov.:

AF XY:

0.0159

AC XY:

1180

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.00545

AC:

226

AN:

41470

American (AMR)

AF:

0.0250

AC:

381

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00404

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00498

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0121

AC:

128

AN:

10586

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0261

AC:

1773

AN:

67952

Other (OTH)

AF:

0.0228

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

128

256

384

512

640

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0223

Hom.:

Bravo

AF:

0.0175

TwinsUK

AF:

0.0291

AC:

108

ALSPAC

AF:

0.0226

AC:

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.0282

AC:

242

ExAC

AF:

0.0158

AC:

1924

Asia WGS

AF:

0.00405

AC:

AN:

3472

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (2)

Atypical hemolytic-uremic syndrome (1)

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

CFHR5 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.67

CADD

Benign

4.3

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0029

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0032

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0093

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

-2.3

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.33

REVEL

Benign

0.13

Sift

Benign

0.17

Sift4G

Benign

0.14

Polyphen

0.82

Vest4

0.051

MPC

0.023

ClinPred

0.024

GERP RS

-6.6

Varity_R

0.022

gMVP

0.54

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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