1-196977739-T-A

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.58+17T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 1,585,286 control chromosomes in the GnomAD database, including 38,437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2931 hom., cov: 32)
  • Exomes 𝑓: 0.22 (35506 hom.)
• Consequence: CFHR5 NM_030787.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.264

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=-0.88).
• BP6: Variant 1-196977739-T-A is Benign according to our data. Variant chr1-196977739-T-A is described in ClinVar as [Benign]. Clinvar id is 1273904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-196977739-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFHR5	NM_030787.4	c.58+17T>A		intron_variant		ENST00000256785.5
CFHR5	XM_011510020.3	c.67+2625T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFHR5	ENST00000256785.5	c.58+17T>A		intron_variant		1	NM_030787.4	P1
CFHR5	ENST00000699466.1	c.-198+2625T>A		intron_variant
CFHR5	ENST00000699468.1	c.-25+59T>A		intron_variant
CFHR5	ENST00000699467.1	n.127+2151T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27724 AN: 152010 Hom.: 2934 Cov.: 32

Gnomad AFR AF: 0.0757

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.292

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.206

GnomAD3 exomes AF: 0.206 AC: 51752 AN: 251352 Hom.: 5798 AF XY: 0.212 AC XY: 28842 AN XY: 135852

Gnomad AFR exome AF: 0.0738

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.287

Gnomad EAS exome AF: 0.167

Gnomad SAS exome AF: 0.212

Gnomad FIN exome AF: 0.214

Gnomad NFE exome AF: 0.239

Gnomad OTH exome AF: 0.221

GnomAD4 exome AF: 0.218 AC: 311935 AN: 1433160 Hom.: 35506 Cov.: 27 AF XY: 0.219 AC XY: 156433 AN XY: 714924

Gnomad4 AFR exome AF: 0.0669

Gnomad4 AMR exome AF: 0.148

Gnomad4 ASJ exome AF: 0.283

Gnomad4 EAS exome AF: 0.154

Gnomad4 SAS exome AF: 0.209

Gnomad4 FIN exome AF: 0.214

Gnomad4 NFE exome AF: 0.227

Gnomad4 OTH exome AF: 0.213

GnomAD4 genome AF: 0.182 AC: 27720 AN: 152126 Hom.: 2931 Cov.: 32 AF XY: 0.182 AC XY: 13543 AN XY: 74364

Gnomad4 AFR AF: 0.0756

Gnomad4 AMR AF: 0.179

Gnomad4 ASJ AF: 0.292

Gnomad4 EAS AF: 0.158

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.222

Gnomad4 NFE AF: 0.236

Gnomad4 OTH AF: 0.206

Alfa AF: 0.192 Hom.: 1922

Bravo AF: 0.173

Asia WGS AF: 0.161 AC: 562 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

CFHR5 deficiency Benign:1

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	-0.88
Cadd	Benign	5.7
Dann	Benign	0.63

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: rs3748557; hg19: chr1-196946869; COSMIC: COSV56819509;