rs565457964

Variant names:

• chr1-196994128-C-CA
• rs565457964
• NM_030787.4:c.486dupA

Your query was ambiguous. Multiple possible variants found:

• chr1-196994128-C-CA
• chr1-196994128-C-CAA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 8P and 4B. PVS1 BS2

The NM_030787.4(CFHR5):​c.486dupA​(p.Glu163ArgfsTer35) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,612,922 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (14 hom.)
• Consequence: CFHR5 NM_030787.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:8 B:2
• Conservation: PhyloP100: -1.46
• Publications: 9 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: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BS2: High AC in GnomAd4 at 328 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030787.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFHR5	NM_030787.4	MANE Select	c.486dupA	p.Glu163ArgfsTer35	frameshift	Exon 4 of 10	NP_110414.1	Q9BXR6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFHR5	ENST00000256785.5	TSL:1 MANE Select	c.486dupA	p.Glu163ArgfsTer35	frameshift	Exon 4 of 10	ENSP00000256785.4	Q9BXR6
	CFHR5	ENST00000875779.1		c.486dupA	p.Glu163ArgfsTer35	frameshift	Exon 4 of 10	ENSP00000545838.1
	CFHR5	ENST00000875778.1		c.486dupA	p.Glu163ArgfsTer35	frameshift	Exon 4 of 9	ENSP00000545837.1

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 328 AN: 151658 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000631

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00181

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00356

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00203 AC: 510 AN: 250704 AF XY: 0.00200

Gnomad AFR exome AF: 0.000618

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00313

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00374 AC: 5468 AN: 1461146 Hom.: 14 Cov.: 30 AF XY: 0.00366 AC XY: 2662 AN XY: 726892

African (AFR) AF: 0.000718 AC: 24 AN: 33434

American (AMR) AF: 0.00159 AC: 71 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.00237 AC: 204 AN: 86188

European-Finnish (FIN) AF: 0.000843 AC: 45 AN: 53386

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5750

European-Non Finnish (NFE) AF: 0.00444 AC: 4933 AN: 1111620

Other (OTH) AF: 0.00292 AC: 176 AN: 60356

GnomAD4 genome AF: 0.00216 AC: 328 AN: 151776 Hom.: 2 Cov.: 32 AF XY: 0.00206 AC XY: 153 AN XY: 74162

African (AFR) AF: 0.000629 AC: 26 AN: 41342

American (AMR) AF: 0.00138 AC: 21 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4812

European-Finnish (FIN) AF: 0.00181 AC: 19 AN: 10480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00356 AC: 242 AN: 67934

Other (OTH) AF: 0.00238 AC: 5 AN: 2102

Alfa AF: 0.000876 Hom.: 1

Bravo AF: 0.00212

EpiCase AF: 0.00338

EpiControl AF: 0.00362

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	-	C3 glomerulonephritis (3)
-	2	1	not provided (3)
-	1	1	CFHR5 deficiency (2)
-	2	-	not specified (2)
-	1	-	Chronic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.5
Mutation Taster		=18/182	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs565457964; hg19: chr1-196963258; COSMIC: COSV56829798;