chr1-196977645-T-C

Position:

• chr1-196977645-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_030787.4(CFHR5):​c.-20T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,596,032 control chromosomes in the GnomAD database, including 14,105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4380 hom., cov: 32)
  • Exomes 𝑓: 0.099 (9725 hom.)
• Consequence: CFHR5 NM_030787.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.00400

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 1-196977645-T-C is Benign according to our data. Variant chr1-196977645-T-C is described in ClinVar as [Benign]. Clinvar id is 294531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-196977645-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFHR5	NM_030787.4	c.-20T>C		5_prime_UTR_variant	1/10	ENST00000256785.5
CFHR5	XM_011510020.3	c.67+2531T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFHR5	ENST00000256785.5	c.-20T>C		5_prime_UTR_variant	1/10	1	NM_030787.4	P1
CFHR5	ENST00000699468.1	c.-60T>C		5_prime_UTR_variant	1/6
CFHR5	ENST00000699466.1	c.-198+2531T>C		intron_variant
CFHR5	ENST00000699467.1	n.127+2057T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27729 AN: 151990 Hom.: 4374 Cov.: 32

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.0862

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.0714

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0896

Gnomad OTH AF: 0.165

GnomAD3 exomes AF: 0.103 AC: 25922 AN: 251402 Hom.: 2491 AF XY: 0.0989 AC XY: 13441 AN XY: 135870

Gnomad AFR exome AF: 0.436

Gnomad AMR exome AF: 0.0589

Gnomad ASJ exome AF: 0.0928

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.101

Gnomad FIN exome AF: 0.0698

Gnomad NFE exome AF: 0.0939

Gnomad OTH exome AF: 0.0952

GnomAD4 exome AF: 0.0989 AC: 142789 AN: 1443924 Hom.: 9725 Cov.: 27 AF XY: 0.0982 AC XY: 70659 AN XY: 719706

Gnomad4 AFR exome AF: 0.442

Gnomad4 AMR exome AF: 0.0635

Gnomad4 ASJ exome AF: 0.0864

Gnomad4 EAS exome AF: 0.000253

Gnomad4 SAS exome AF: 0.100

Gnomad4 FIN exome AF: 0.0676

Gnomad4 NFE exome AF: 0.0947

Gnomad4 OTH exome AF: 0.108

GnomAD4 genome AF: 0.182 AC: 27754 AN: 152108 Hom.: 4380 Cov.: 32 AF XY: 0.180 AC XY: 13346 AN XY: 74338

Gnomad4 AFR AF: 0.433

Gnomad4 AMR AF: 0.114

Gnomad4 ASJ AF: 0.0862

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.100

Gnomad4 FIN AF: 0.0714

Gnomad4 NFE AF: 0.0896

Gnomad4 OTH AF: 0.164

Alfa AF: 0.110 Hom.: 2350

Bravo AF: 0.196

Asia WGS AF: 0.0710 AC: 246 AN: 3478

EpiCase AF: 0.0939

EpiControl AF: 0.0898

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	This variant is associated with the following publications: (PMID: 21784901, 16299065) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

CFHR5 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Atypical hemolytic-uremic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 05, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.8
DANN	Benign	0.79

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: rs9427662; hg19: chr1-196946775;