1-196977645-T-C

Variant names:

• chr1-196977645-T-C
• rs9427662
• NM_030787.4:c.-20T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate 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
• Publications: 12 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.031).
• 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.
• 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 rank	MANE	Protein	UniProt
CFHR5	NM_030787.4	c.-20T>C		5_prime_UTR_variant	Exon 1 of 10	ENST00000256785.5	NP_110414.1
CFHR5	XM_011510020.3	c.67+2531T>C		intron_variant	Intron 1 of 9		XP_011508322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFHR5	ENST00000256785.5	c.-20T>C		5_prime_UTR_variant	Exon 1 of 10	1	NM_030787.4	ENSP00000256785.4
CFHR5	ENST00000699468.1	c.-60T>C		5_prime_UTR_variant	Exon 1 of 6			ENSP00000514394.1
CFHR5	ENST00000699466.1	c.-198+2531T>C		intron_variant	Intron 1 of 9			ENSP00000514393.1
CFHR5	ENST00000699467.1	n.127+2057T>C		intron_variant	Intron 1 of 9

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

GnomAD2 exomes AF: 0.103 AC: 25922 AN: 251402 AF XY: 0.0989

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 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

African (AFR) AF: 0.442 AC: 14539 AN: 32870

American (AMR) AF: 0.0635 AC: 2840 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0864 AC: 2244 AN: 25986

East Asian (EAS) AF: 0.000253 AC: 10 AN: 39552

South Asian (SAS) AF: 0.100 AC: 8588 AN: 85778

European-Finnish (FIN) AF: 0.0676 AC: 3609 AN: 53388

Middle Eastern (MID) AF: 0.128 AC: 734 AN: 5714

European-Non Finnish (NFE) AF: 0.0947 AC: 103784 AN: 1096186

Other (OTH) AF: 0.108 AC: 6441 AN: 59748

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

African (AFR) AF: 0.433 AC: 17960 AN: 41460

American (AMR) AF: 0.114 AC: 1742 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0862 AC: 299 AN: 3468

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.100 AC: 482 AN: 4812

European-Finnish (FIN) AF: 0.0714 AC: 756 AN: 10582

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0896 AC: 6095 AN: 68002

Other (OTH) AF: 0.164 AC: 345 AN: 2110

Alfa AF: 0.129 Hom.: 4923

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

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21784901, 16299065) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Atypical hemolytic-uremic syndrome Benign:1

Oct 05, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.8
DANN	Benign	0.79
PhyloP100		0.0040
PromoterAI		0.030	Neutral
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9427662; hg19: chr1-196946775;