1-196994128-C-CA

Position:

• chr1-196994128-C-CA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_030787.4(CFHR5):​c.486dup​(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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7 B:2
• Conservation: PhyloP100: -1.46

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 1-196994128-C-CA is Benign according to our data. Variant chr1-196994128-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 402534.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=7}.
• BS2: High AC in GnomAd4 at 328 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFHR5	NM_030787.4	c.486dup	p.Glu163ArgfsTer35	frameshift_variant	4/10	ENST00000256785.5	NP_110414.1
CFHR5	XM_011510020.3	c.495dup	p.Glu166ArgfsTer35	frameshift_variant	4/10		XP_011508322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFHR5	ENST00000256785.5	c.486dup	p.Glu163ArgfsTer35	frameshift_variant	4/10	1	NM_030787.4	ENSP00000256785	P1
CFHR5	ENST00000699466.1	c.231dup	p.Glu78ArgfsTer35	frameshift_variant	4/10			ENSP00000514393
CFHR5	ENST00000699468.1	c.-24-1979dup		intron_variant				ENSP00000514394
CFHR5	ENST00000699467.1	n.555dup		non_coding_transcript_exon_variant	4/10

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 328 AN: 151658 Hom.: 2 Cov.: 32

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

GnomAD3 exomes AF: 0.00203 AC: 510 AN: 250704 Hom.: 0 AF XY: 0.00200 AC XY: 271 AN XY: 135512

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 SAS exome AF: 0.00187

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.: 14 Cov.: 30 AF XY: 0.00366 AC XY: 2662 AN XY: 726892

Gnomad4 AFR exome AF: 0.000718

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00237

Gnomad4 FIN exome AF: 0.000843

Gnomad4 NFE exome AF: 0.00444

Gnomad4 OTH exome AF: 0.00292

GnomAD4 genome AF: 0.00216 AC: 328 AN: 151776 Hom.: 2 Cov.: 32 AF XY: 0.00206 AC XY: 153 AN XY: 74162

Gnomad4 AFR AF: 0.000629

Gnomad4 AMR AF: 0.00138

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00181

Gnomad4 NFE AF: 0.00356

Gnomad4 OTH AF: 0.00238

Alfa AF: 0.000876 Hom.: 1

Bravo AF: 0.00212

EpiCase AF: 0.00338

EpiControl AF: 0.00362

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:7 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2020	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) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 30, 2021	- -

CFHR5 deficiency Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Mar 19, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 06, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 18, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 04, 2022	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, which are commonly known mechanisms 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 is approximately 50 fold of the estimated maximal expected allele frequency for a pathogenic variant in CFHR5 causing CFHR5 Deficiency phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. 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. Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=5), likely benign (n=1), benign (n=1) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

C3 glomerulonephritis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2012

- -

Chronic kidney disease Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Cavalleri Lab, Royal College of Surgeons in Ireland

May 28, 2020

PVS1, BS1 -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs565457964; hg19: chr1-196963258;