rs368209619

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_030787.4(CFHR5):c.678delA(p.Glu226AspfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,612,820 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

CFHR5
NM_030787.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: -0.430

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFHR5	NM_030787.4 link	c.678delA	p.Glu226AspfsTer7	frameshift_variant	Exon 5 of 10	ENST00000256785.5	NP_110414.1	Q9BXR6
CFHR5	XM_011510020.3 link	c.687delA	p.Glu229AspfsTer7	frameshift_variant	Exon 5 of 10		XP_011508322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CFHR5	ENST00000256785.5 link	c.678delA	p.Glu226AspfsTer7	frameshift_variant	Exon 5 of 10	1	NM_030787.4	ENSP00000256785.4	Q9BXR6
CFHR5	ENST00000699466.1 link	c.423delA	p.Glu141AspfsTer7	frameshift_variant	Exon 5 of 10			ENSP00000514393.1	A0A8V8TNA3
CFHR5	ENST00000699468.1 link	c.-24-327delA		intron_variant	Intron 1 of 5			ENSP00000514394.1	A0A8V8TNF4
CFHR5	ENST00000699467.1 link	n.747delA		non_coding_transcript_exon_variant	Exon 5 of 10

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251136

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1460764

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

726738

show subpopulations

Gnomad4 AFR exome

AF:

0.000718

AC:

AN:

33440

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44694

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26120

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39646

Gnomad4 SAS exome

AF:

0.0000348

AC:

AN:

86238

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53408

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

1111094

Gnomad4 Remaining exome

AF:

0.000282

AC:

AN:

60364

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

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

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.0000725

AC:

0.0000724603

AN:

0.0000724603

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.000479

AC:

0.000478927

AN:

0.000478927

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

CFHR5 deficiency

Pathogenic:1Uncertain:1

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 17, 2016

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Loss of function mutations in the CHFR5 gene are known to be a cause of autosomic dominant nephropathy. -

not specified

Uncertain:1

Mar 03, 2025

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.678delA (p.Glu226AspfsX7) 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 8e-06 in 251136 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.678delA has been reported in the literature in at least one individual affected with atypical hemolytic uremic syndrome and one individual with C3 glomerulopathy (e.g., Rydberg_2023). Both individuals also carried other variants in CFHR5 as well as variants in other genes associated with kidney disease. This variant has also been reported in at least one individual with infertility (e.g., Dougherty_2023). These report(s) do not provide unequivocal conclusions about association of the variant with CFHR5 Deficiency. 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: 36920765, 37744338). ClinVar contains an entry for this variant (Variation ID: 226110). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Oct 20, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=41/159

disease causing (ClinVar)

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over