1-196982900-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030787.4(CFHR5):c.74T>A(p.Phe25Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CFHR5 NM_030787.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2100113).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFHR5	NM_030787.4	c.74T>A	p.Phe25Tyr	missense_variant	2/10	ENST00000256785.5
CFHR5	XM_011510020.3	c.83T>A	p.Phe28Tyr	missense_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFHR5	ENST00000256785.5	c.74T>A	p.Phe25Tyr	missense_variant	2/10	1	NM_030787.4	P1
CFHR5	ENST00000699466.1	c.-182T>A		5_prime_UTR_variant	2/10
CFHR5	ENST00000699468.1	c.-25+5220T>A		intron_variant
CFHR5	ENST00000699467.1	n.143T>A		non_coding_transcript_exon_variant	2/10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251056 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135762

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461708 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727164

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 17, 2023

This sequence change replaces phenylalanine, which is neutral and non-polar, with tyrosine, which is neutral and polar, at codon 25 of the CFHR5 protein (p.Phe25Tyr). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CFHR5-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0062	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.076
Sift	Benign	0.18	T
Sift4G	Benign	0.52	T
Polyphen		0.76	P
Vest4		0.23
MutPred		0.48		Loss of methylation at K27 (P = 0.0806);
MVP		0.62
MPC		0.017
ClinPred		0.37	T
GERP RS		2.5
Varity_R		0.28
gMVP		0.71

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

Other links and lift over

dbSNP: rs1290211561; hg19: chr1-196952030;