1-196994128-C-CA

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 8P and 4B. PVS1BS2

The NM_030787.4(CFHR5):c.486dupA(p.Glu163ArgfsTer35) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,612,922 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0022 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 14 hom. )

Consequence

CFHR5
NM_030787.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8B:2

Conservation

PhyloP100: -1.46

Publications

9 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: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BS2

High AC in GnomAd4 at 328 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFHR5	NM_030787.4 link	c.486dupA	p.Glu163ArgfsTer35	frameshift_variant	Exon 4 of 10	ENST00000256785.5	NP_110414.1	Q9BXR6
CFHR5	XM_011510020.3 link	c.495dupA	p.Glu166ArgfsTer35	frameshift_variant	Exon 4 of 10		XP_011508322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CFHR5	ENST00000256785.5 link	c.486dupA	p.Glu163ArgfsTer35	frameshift_variant	Exon 4 of 10	1	NM_030787.4	ENSP00000256785.4	Q9BXR6
CFHR5	ENST00000699466.1 link	c.231dupA	p.Glu78ArgfsTer35	frameshift_variant	Exon 4 of 10			ENSP00000514393.1	A0A8V8TNA3
CFHR5	ENST00000699467.1 link	n.555dupA		non_coding_transcript_exon_variant	Exon 4 of 10
CFHR5	ENST00000699468.1 link	c.-24-1979dupA		intron_variant	Intron 1 of 5			ENSP00000514394.1	A0A8V8TNF4

Frequencies

GnomAD3 genomes

AF:

0.00216

AC:

328

AN:

151658

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000631

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00138

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.00181

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00356

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.00203

AC:

510

AN:

250704

AF XY:

0.00200

show subpopulations

Gnomad AFR exome

AF:

0.000618

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000878

Gnomad NFE exome

AF:

0.00313

Gnomad OTH exome

AF:

0.00213

GnomAD4 exome

AF:

0.00374

AC:

5468

AN:

1461146

Hom.:

Cov.:

AF XY:

0.00366

AC XY:

2662

AN XY:

726892

show subpopulations

African (AFR)

AF:

0.000718

AC:

AN:

33434

American (AMR)

AF:

0.00159

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.000268

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39584

South Asian (SAS)

AF:

0.00237

AC:

204

AN:

86188

European-Finnish (FIN)

AF:

0.000843

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00444

AC:

4933

AN:

1111620

Other (OTH)

AF:

0.00292

AC:

176

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

254

508

763

1017

1271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

202

404

606

808

1010

<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:

0.00216

AC:

328

AN:

151776

Hom.:

Cov.:

AF XY:

0.00206

AC XY:

153

AN XY:

74162

show subpopulations

African (AFR)

AF:

0.000629

AC:

AN:

41342

American (AMR)

AF:

0.00138

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5174

South Asian (SAS)

AF:

0.00187

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00181

AC:

AN:

10480

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00356

AC:

242

AN:

67934

Other (OTH)

AF:

0.00238

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000876

Hom.:

Bravo

AF:

0.00212

EpiCase

AF:

0.00338

EpiControl

AF:

0.00362

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:8Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 30, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in individuals with renal disease, however, it has also been reported in clinically asymptomatic individuals (Monteferrante et al., 2007; Vernon et al., 2012; Figueres et al., 2014; Schapiro et al., 2019); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; Observed in one homozygous clinically unaffected adult relative of an individual referred for genetic testing at GeneDx; Also known as c.485dupA and Asn1975Stop using alternate nomenclature; This variant is associated with the following publications: (PMID: 30295827, 31664448, 22503529, 25260719, 17000000, 31980526) -

CFHR5 deficiency

Uncertain:2Benign:1

Aug 06, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 19, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

C3 glomerulonephritis

Pathogenic:1Uncertain:1

Jul 01, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jun 29, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

not specified

Uncertain:2

Oct 18, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Glu163ArgfsX3 5 variant in CFHR5 (also reported as p.Glu163Arg and p.Asn197Stop) has been prev iously reported in at least two heterozygous individuals with CFHR5-deficiency a nd complement-mediated kidney diseases, as well as at least three asymptomatic i ndividuals (1 control and 2 family members of 1 of the heterozygotes; Monteferra nte 2007, Vernon 2012, and Figueres 2014). This variant has also been reported i n ClinVar (Variation ID#402534). It has been identified in 0.31% (395/126014) Eu ropean chromosomes by the Genome Aggregation Database (http://gnomad.broadinstit ute.org; rs565457964). This variant is predicted to cause a frameshift, which al ters the protein?s amino acid sequence beginning at position 163 and leads to a premature termination codon 35 amino acids downstream. This alteration is then p redicted to lead to a truncated or absent protein. In summary, while the clinica l significance of the p.Glu163ArgfsX35 variant is uncertain, these data suggest that it is more likely to be benign. -

Oct 02, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CFHR5 c.486dupA (p.Glu163ArgfsX35) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however current evidence is not sufficient to establish loss of function as a mechanism for disease. The variant allele was found at a frequency of 0.002 in 251100 control chromosomes, predominantly at a frequency of 0.0031 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in CFHR5 causing CFHR5 Deficiency phenotype. c.486dupA has been reported in the literature in individuals affected with CFHR5 Deficiency as well as in at least three healthy individuals (Monteferrante_2006, Vernon_2012, Figueres_2014, Benson_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32723786, 25260719, 31664448, 17000000, 28750028, 30295827, 22527104, 28054583, 22503529). ClinVar contains an entry for this variant (Variation ID: 402534). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Chronic kidney disease

Uncertain:1

May 28, 2020

Cavalleri Lab, Royal College of Surgeons in Ireland

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

PVS1, BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.5

Mutation Taster

=18/182

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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