chr1-196994128-C-CAA

Position:

chr1-196994128-C-CAA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_030787.4(CFHR5):c.485_486dup(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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:5

Conservation

PhyloP100: -1.46

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

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 id is 294541.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=2}.

BS2

High AC in GnomAd4 at 845 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFHR5	NM_030787.4 linkuse as main transcript	c.485_486dup	p.Glu163LysfsTer10	frameshift_variant	4/10	ENST00000256785.5	NP_110414.1
CFHR5	XM_011510020.3 linkuse as main transcript	c.494_495dup	p.Glu166LysfsTer10	frameshift_variant	4/10		XP_011508322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CFHR5	ENST00000256785.5 linkuse as main transcript	c.485_486dup	p.Glu163LysfsTer10	frameshift_variant	4/10	1	NM_030787.4	ENSP00000256785	P1
CFHR5	ENST00000699466.1 linkuse as main transcript	c.230_231dup	p.Glu78LysfsTer10	frameshift_variant	4/10			ENSP00000514393
CFHR5	ENST00000699468.1 linkuse as main transcript	c.-24-1980_-24-1979dup		intron_variant				ENSP00000514394
CFHR5	ENST00000699467.1 linkuse as main transcript	n.554_555dup		non_coding_transcript_exon_variant	4/10

Frequencies

GnomAD3 genomes

AF:

0.00557

AC:

845

AN:

151652

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00632

AC:

1584

AN:

250704

Hom.:

AF XY:

0.00616

AC XY:

835

AN XY:

135512

show subpopulations

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 SAS exome

AF:

0.000131

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.:

Cov.:

AF XY:

0.00482

AC XY:

3502

AN XY:

726874

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.000421

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.000302

Gnomad4 FIN exome

AF:

0.0406

Gnomad4 NFE exome

AF:

0.00416

Gnomad4 OTH exome

AF:

0.00330

GnomAD4 genome

AF:

0.00557

AC:

845

AN:

151770

Hom.:

Cov.:

AF XY:

0.00697

AC XY:

517

AN XY:

74156

show subpopulations

Gnomad4 AFR

AF:

0.000339

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0383

Gnomad4 NFE

AF:

0.00609

Gnomad4 OTH

AF:

0.00571

Alfa

AF:

0.00497

Hom.:

Bravo

AF:

0.00209

EpiCase

AF:

0.00496

EpiControl

AF:

0.00261

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CFHR5: BS1, BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

CFHR5 deficiency

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	May 08, 2019	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3,PP5,BS1. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 11, 2017	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Kidney disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 16, 2017

- -

Mesangiocapillary glomerulonephritis, type II

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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