chr1-196994128-C-CAA

Variant names:

• chr1-196994128-C-CAA
• rs565457964
• NM_030787.4:c.485_486dupAA

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 8P and 5B. PVS1 BP6 BS2

The NM_030787.4(CFHR5):​c.485_486dupAA​(p.Glu163LysfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00491 in 1,612,894 control chromosomes in the GnomAD database, including 84 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0056 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (66 hom.)
• Consequence: CFHR5 NM_030787.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5
• 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 3 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 1-196994128-C-CAA is Benign according to our data. Variant chr1-196994128-C-CAA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 294541.
• BS2: High AC in GnomAd4 at 845 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.485_486dupAA	p.Glu163LysfsTer10	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.485_486dupAA	p.Glu163LysfsTer10	frameshift	Exon 4 of 10	ENSP00000256785.4	Q9BXR6
	CFHR5	ENST00000875779.1		c.485_486dupAA	p.Glu163LysfsTer10	frameshift	Exon 4 of 10	ENSP00000545838.1
	CFHR5	ENST00000875778.1		c.485_486dupAA	p.Glu163LysfsTer10	frameshift	Exon 4 of 9	ENSP00000545837.1

Frequencies

GnomAD3 genomes AF: 0.00557 AC: 845 AN: 151652 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.000340

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0383

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00609

Gnomad OTH AF: 0.00577

GnomAD2 exomes AF: 0.00632 AC: 1584 AN: 250704 AF XY: 0.00616

Gnomad AFR exome AF: 0.000556

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0407

Gnomad NFE exome AF: 0.00554

Gnomad OTH exome AF: 0.00622

GnomAD4 exome AF: 0.00484 AC: 7070 AN: 1461124 Hom.: 66 Cov.: 30 AF XY: 0.00482 AC XY: 3502 AN XY: 726874

African (AFR) AF: 0.000359 AC: 12 AN: 33434

American (AMR) AF: 0.000514 AC: 23 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26116

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39584

South Asian (SAS) AF: 0.000302 AC: 26 AN: 86188

European-Finnish (FIN) AF: 0.0406 AC: 2167 AN: 53376

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5750

European-Non Finnish (NFE) AF: 0.00416 AC: 4628 AN: 1111610

Other (OTH) AF: 0.00330 AC: 199 AN: 60356

GnomAD4 genome AF: 0.00557 AC: 845 AN: 151770 Hom.: 18 Cov.: 32 AF XY: 0.00697 AC XY: 517 AN XY: 74156

African (AFR) AF: 0.000339 AC: 14 AN: 41342

American (AMR) AF: 0.000197 AC: 3 AN: 15256

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.0383 AC: 401 AN: 10474

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00609 AC: 414 AN: 67934

Other (OTH) AF: 0.00571 AC: 12 AN: 2102

Alfa AF: 0.00497 Hom.: 1

Bravo AF: 0.00209

EpiCase AF: 0.00496

EpiControl AF: 0.00261

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	2	not provided (5)
-	2	-	CFHR5 deficiency (2)
-	-	1	Kidney disorder (1)
-	-	1	Mesangiocapillary glomerulonephritis, type II (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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

Splicing

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

Other links and lift over

dbSNP: rs565457964; hg19: chr1-196963258;