NM_030787.4:c.1308G>T

Variant names:

• chr1-197002642-G-T
• rs201265664
• NM_030787.4:c.1308G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_030787.4(CFHR5):​c.1308G>T​(p.Trp436Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CFHR5 NM_030787.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1 O:1
• Conservation: PhyloP100: 5.31
• Publications: 2 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFHR5	NM_030787.4	MANE Select	c.1308G>T	p.Trp436Cys	missense	Exon 8 of 10	NP_110414.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFHR5	ENST00000256785.5	TSL:1 MANE Select	c.1308G>T	p.Trp436Cys	missense	Exon 8 of 10	ENSP00000256785.4
	CFHR5	ENST00000699466.1		c.1053G>T	p.Trp351Cys	missense	Exon 8 of 10	ENSP00000514393.1
	CFHR5	ENST00000699468.1		c.402G>T	p.Trp134Cys	missense	Exon 4 of 6	ENSP00000514394.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251056 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460998 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726872

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111406

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Variant of unknown significance Uncertain:1

Jul 01, 2012

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Other:1

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Benign	0.94
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.024
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		5.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-12	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.82		Gain of disorder (P = 0.0274)
MVP		0.95
MPC		0.13
ClinPred		0.95	D
GERP RS		2.8
Varity_R		0.48
gMVP		0.96
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs201265664; hg19: chr1-196971772;