NM_030787.4:c.1067G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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:10

Conservation

PhyloP100: -2.28

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 made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 402533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-196998224-G-A is described in Lovd as [Benign]. Variant chr1-196998224-G-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2602 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFHR5	NM_030787.4 link	c.1067G>A	p.Arg356His	missense_variant	Exon 7 of 10	ENST00000256785.5	NP_110414.1	Q9BXR6
CFHR5	XM_011510020.3 link	c.1076G>A	p.Arg359His	missense_variant	Exon 7 of 10		XP_011508322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFHR5	ENST00000256785.5 link	c.1067G>A	p.Arg356His	missense_variant	Exon 7 of 10	1	NM_030787.4	ENSP00000256785.4		Q9BXR6

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

GnomAD3 exomes

AF:

0.0163

AC:

4073

AN:

249494

Hom.:

AF XY:

0.0165

AC XY:

2224

AN XY:

134950

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 SAS exome

AF:

0.00283

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

Gnomad4 AFR exome

AF:

0.00405

Gnomad4 AMR exome

AF:

0.0192

Gnomad4 ASJ exome

AF:

0.00484

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00340

Gnomad4 FIN exome

AF:

0.0150

Gnomad4 NFE exome

AF:

0.0286

Gnomad4 OTH exome

AF:

0.0245

GnomAD4 genome

AF:

0.0171

AC:

2602

AN:

152062

Hom.:

Cov.:

AF XY:

0.0159

AC XY:

1180

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00545

Gnomad4 AMR

AF:

0.0250

Gnomad4 ASJ

AF:

0.00404

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00498

Gnomad4 FIN

AF:

0.0121

Gnomad4 NFE

AF:

0.0261

Gnomad4 OTH

AF:

0.0228

Alfa

AF:

0.0226

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

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Jun 10, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFHR5: BP4, BS1, BS2 -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 272/13000=2% -

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

CFHR5 deficiency

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Atypical hemolytic-uremic syndrome

Benign:1

Mar 15, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.67

CADD

Benign

4.3

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

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

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

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