rs185709089

Positions:

• chr1-196983956-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_030787.4(CFHR5):​c.254-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0044 in 1,601,726 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (19 hom.)
• Consequence: CFHR5 NM_030787.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003649
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.06

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-196983956-C-T is Benign according to our data. Variant chr1-196983956-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 599457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-196983956-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 559 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFHR5	NM_030787.4	c.254-5C>T		splice_region_variant, intron_variant		ENST00000256785.5	NP_110414.1
CFHR5	XM_011510020.3	c.263-5C>T		splice_region_variant, intron_variant			XP_011508322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFHR5	ENST00000256785.5	c.254-5C>T		splice_region_variant, intron_variant		1	NM_030787.4	ENSP00000256785.4
CFHR5	ENST00000699466.1	c.-2-5C>T		splice_region_variant, intron_variant				ENSP00000514393.1
CFHR5	ENST00000699468.1	c.-25+6276C>T		intron_variant				ENSP00000514394.1
CFHR5	ENST00000699467.1	n.323-5C>T		splice_region_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.00368 AC: 558 AN: 151780 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00578

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00731

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00484

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00317 AC: 790 AN: 249462 Hom.: 0 AF XY: 0.00307 AC XY: 414 AN XY: 134896

Gnomad AFR exome AF: 0.000991

Gnomad AMR exome AF: 0.00198

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000658

Gnomad FIN exome AF: 0.00742

Gnomad NFE exome AF: 0.00438

Gnomad OTH exome AF: 0.00444

GnomAD4 exome AF: 0.00447 AC: 6487 AN: 1449832 Hom.: 19 Cov.: 28 AF XY: 0.00432 AC XY: 3118 AN XY: 721592

Gnomad4 AFR exome AF: 0.000662

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.000539

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000742

Gnomad4 FIN exome AF: 0.00669

Gnomad4 NFE exome AF: 0.00516

Gnomad4 OTH exome AF: 0.00378

GnomAD4 genome AF: 0.00368 AC: 559 AN: 151894 Hom.: 1 Cov.: 32 AF XY: 0.00375 AC XY: 278 AN XY: 74226

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00578

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00731

Gnomad4 NFE AF: 0.00484

Gnomad4 OTH AF: 0.00522

Alfa AF: 0.00382 Hom.: 0

Bravo AF: 0.00318

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 25, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 06, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Jul 17, 2017	BS1, BP4; This alteration has an allele frequency that is greater than expected for the associated disease, and is predicted to be tolerated by multiple functional prediction tools. -

Kidney disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 01, 2017

- -

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -

CFHR5 deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.80
DANN	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000036
dbscSNV1_RF	Benign	0.0
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: rs185709089; hg19: chr1-196953086;