1-196977587-CTG-C

Variant names:

• chr1-196977587-CTG-C
• rs551454946
• NM_030787.4:c.-76_-75delGT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_030787.4(CFHR5):​c.-76_-75delGT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000858 in 1,126,836 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (2 hom.)
• Consequence: CFHR5 NM_030787.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.746
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 572 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFHR5	NM_030787.4	c.-76_-75delGT		5_prime_UTR_variant	Exon 1 of 10	ENST00000256785.5	NP_110414.1
CFHR5	XM_011510020.3	c.67+2475_67+2476delGT		intron_variant	Intron 1 of 9		XP_011508322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFHR5	ENST00000256785.5	c.-76_-75delGT		5_prime_UTR_variant	Exon 1 of 10	1	NM_030787.4	ENSP00000256785.4
CFHR5	ENST00000699468.1	c.-116_-115delGT		5_prime_UTR_variant	Exon 1 of 6			ENSP00000514394.1
CFHR5	ENST00000699466.1	c.-198+2475_-198+2476delGT		intron_variant	Intron 1 of 9			ENSP00000514393.1
CFHR5	ENST00000699467.1	n.127+2001_127+2002delGT		intron_variant	Intron 1 of 9

Frequencies

GnomAD3 genomes AF: 0.00373 AC: 568 AN: 152090 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000894 AC: 224 AN: 250536 AF XY: 0.000613

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.000725

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000405 AC: 395 AN: 974628 Hom.: 2 AF XY: 0.000328 AC XY: 166 AN XY: 506856

African (AFR) AF: 0.0129 AC: 306 AN: 23656

American (AMR) AF: 0.000680 AC: 30 AN: 44104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23064

East Asian (EAS) AF: 0.00 AC: 0 AN: 37384

South Asian (SAS) AF: 0.000105 AC: 8 AN: 76178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4816

European-Non Finnish (NFE) AF: 0.00000299 AC: 2 AN: 667952

Other (OTH) AF: 0.00110 AC: 49 AN: 44396

GnomAD4 genome AF: 0.00376 AC: 572 AN: 152208 Hom.: 1 Cov.: 32 AF XY: 0.00348 AC XY: 259 AN XY: 74426

African (AFR) AF: 0.0133 AC: 551 AN: 41530

American (AMR) AF: 0.00105 AC: 16 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2106

Alfa AF: 0.00191 Hom.: 0

Bravo AF: 0.00442

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mesangiocapillary glomerulonephritis, type II Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.75
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs551454946; hg19: chr1-196946717;