rs751010317

Positions:

chr1-196998150-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_030787.4(CFHR5):c.993C>A(p.Cys331*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000584 in 1,558,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

CFHR5
NM_030787.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:1

Conservation

PhyloP100: -0.922

Variant links:

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 links:

CFHR5 (HGNC:):

CFHR5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 87 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFHR5	NM_030787.4 linkuse as main transcript	c.993C>A	p.Cys331*	stop_gained	7/10	ENST00000256785.5	NP_110414.1	Q9BXR6
CFHR5	XM_011510020.3 linkuse as main transcript	c.1002C>A	p.Cys334*	stop_gained	7/10		XP_011508322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFHR5	ENST00000256785.5 linkuse as main transcript	c.993C>A	p.Cys331*	stop_gained	7/10	1	NM_030787.4	ENSP00000256785.4		Q9BXR6

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151916

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000121

AC:

AN:

182146

Hom.:

AF XY:

0.000154

AC XY:

AN XY:

97488

show subpopulations

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 SAS exome

AF:

0.000812

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000418

GnomAD4 exome

AF:

0.0000618

AC:

AN:

1407028

Hom.:

Cov.:

AF XY:

0.0000919

AC XY:

AN XY:

696444

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000965

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000555

Gnomad4 OTH exome

AF:

0.0000344

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151916

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74198

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000587

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

CFHR5 deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 18, 2017

- -

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Dec 05, 2018

The CFHR5 c.993C>A (p.Cys331Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease. -

C3 glomerulonephritis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 31, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Benign

0.95

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.010

Vest4

0.71

GERP RS

-0.72

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over