chr1-196977290-T-A

Variant names:

• chr1-196977290-T-A
• rs9427660
• ENST00000699466.1:c.-198+2176T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000699466.1(CFHR5):​c.-198+2176T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 139,436 control chromosomes in the GnomAD database, including 4,256 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.19 (4256 hom., cov: 29)
• Consequence: CFHR5 ENST00000699466.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.531
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 1-196977290-T-A is Benign according to our data. Variant chr1-196977290-T-A is described in ClinVar as [Benign]. Clinvar id is 1268818.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFHR5	XM_011510020.3	c.67+2176T>A		intron_variant	Intron 1 of 9		XP_011508322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFHR5	ENST00000699466.1	c.-198+2176T>A		intron_variant	Intron 1 of 9			ENSP00000514393.1
CFHR5	ENST00000699467.1	n.127+1702T>A		intron_variant	Intron 1 of 9

Frequencies

GnomAD3 genomes AF: 0.195 AC: 27142 AN: 139390 Hom.: 4252 Cov.: 29

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.0457

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.0908

Gnomad EAS AF: 0.00139

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0825

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0926

Gnomad OTH AF: 0.176

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.195 AC: 27154 AN: 139436 Hom.: 4256 Cov.: 29 AF XY: 0.194 AC XY: 13046 AN XY: 67184

African (AFR) AF: 0.442 AC: 17513 AN: 39582

American (AMR) AF: 0.133 AC: 1719 AN: 12878

Ashkenazi Jewish (ASJ) AF: 0.0908 AC: 299 AN: 3294

East Asian (EAS) AF: 0.00139 AC: 4 AN: 2876

South Asian (SAS) AF: 0.118 AC: 470 AN: 3980

European-Finnish (FIN) AF: 0.0825 AC: 704 AN: 8532

Middle Eastern (MID) AF: 0.107 AC: 29 AN: 270

European-Non Finnish (NFE) AF: 0.0926 AC: 6037 AN: 65184

Other (OTH) AF: 0.174 AC: 338 AN: 1942

Alfa AF: 0.0254 Hom.: 21

Asia WGS AF: 0.0660 AC: 226 AN: 3424

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 2021

GeneDx

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	-0.94
CADD	Benign	1.1
DANN	Benign	0.41
PhyloP100		-0.53
PromoterAI		0.019	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9427660; hg19: chr1-196946420;