chr1-196977318-G-A

Variant names:

• chr1-196977318-G-A
• rs9427942
• ENST00000699466.1:c.-198+2204G>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+2204G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 150,074 control chromosomes in the GnomAD database, including 4,293 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.18 (4293 hom., cov: 31)
• Consequence: CFHR5 ENST00000699466.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.15
• Publications: 1 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=-0.93).
• BP6: Variant 1-196977318-G-A is Benign according to our data. Variant chr1-196977318-G-A is described in ClinVar as [Benign]. Clinvar id is 1274652.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFHR5	XM_011510020.3	c.67+2204G>A		intron_variant	Intron 1 of 9		XP_011508322.1
CFHR5	NM_030787.4	c.-347G>A		upstream_gene_variant		ENST00000256785.5	NP_110414.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFHR5	ENST00000699466.1	c.-198+2204G>A		intron_variant	Intron 1 of 9			ENSP00000514393.1
CFHR5	ENST00000699467.1	n.127+1730G>A		intron_variant	Intron 1 of 9
CFHR5	ENST00000256785.5	c.-347G>A		upstream_gene_variant		1	NM_030787.4	ENSP00000256785.4
CFHR5	ENST00000699468.1	c.-387G>A		upstream_gene_variant				ENSP00000514394.1

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27329 AN: 150040 Hom.: 4289 Cov.: 31

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.0862

Gnomad EAS AF: 0.000776

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.0723

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0893

Gnomad OTH AF: 0.166

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

GnomAD4 genome AF: 0.182 AC: 27344 AN: 150074 Hom.: 4293 Cov.: 31 AF XY: 0.180 AC XY: 13143 AN XY: 73150

African (AFR) AF: 0.433 AC: 17669 AN: 40844

American (AMR) AF: 0.114 AC: 1728 AN: 15112

Ashkenazi Jewish (ASJ) AF: 0.0862 AC: 299 AN: 3470

East Asian (EAS) AF: 0.000778 AC: 4 AN: 5140

South Asian (SAS) AF: 0.101 AC: 477 AN: 4738

European-Finnish (FIN) AF: 0.0723 AC: 710 AN: 9816

Middle Eastern (MID) AF: 0.103 AC: 29 AN: 282

European-Non Finnish (NFE) AF: 0.0893 AC: 6043 AN: 67676

Other (OTH) AF: 0.165 AC: 344 AN: 2084

Alfa AF: 0.156 Hom.: 571

Bravo AF: 0.196

Asia WGS AF: 0.0690 AC: 239 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.2
DANN	Benign	0.38
PhyloP100		-1.2
PromoterAI		-0.026	Neutral

Splicing

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

Other links and lift over

dbSNP: rs9427942; hg19: chr1-196946448;