Genetic Variant CFHR5:p.Leu3Phe (chr1-196977671-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_030787.4(CFHR5):c.7C>T(p.Leu3Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L3V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CFHR5
NM_030787.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.570

Publications

0 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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21651283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFHR5	NM_030787.4 link	c.7C>T	p.Leu3Phe	missense_variant	Exon 1 of 10	ENST00000256785.5	NP_110414.1	Q9BXR6
CFHR5	XM_011510020.3 link	c.67+2557C>T		intron_variant	Intron 1 of 9		XP_011508322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CFHR5	ENST00000256785.5 link	c.7C>T	p.Leu3Phe	missense_variant	Exon 1 of 10	1	NM_030787.4	ENSP00000256785.4	Q9BXR6
CFHR5	ENST00000699468.1 link	c.-34C>T		5_prime_UTR_variant	Exon 1 of 6			ENSP00000514394.1	A0A8V8TNF4
CFHR5	ENST00000699466.1 link	c.-198+2557C>T		intron_variant	Intron 1 of 9			ENSP00000514393.1	A0A8V8TNA3
CFHR5	ENST00000699467.1 link	n.127+2083C>T		intron_variant	Intron 1 of 9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460122

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726494

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33434

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39628

South Asian (SAS)

AF:

0.00

AC:

AN:

86176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110546

Other (OTH)

AF:

0.00

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

2.8

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.015

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.0033

LIST_S2

Benign

0.44

M_CAP

Benign

0.0044

MetaRNN

Benign

0.22

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PhyloP100

-0.57

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.2

REVEL

Benign

0.092

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.035

Polyphen

0.99

Vest4

0.25

MutPred

0.57

Loss of stability (P = 0.1411);

MVP

0.37

MPC

0.069

ClinPred

0.36

GERP RS

-1.8

PromoterAI

-0.0043

Neutral

(source)

Varity_R

0.19

gMVP

0.59

Mutation Taster

=98/2

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over