rs1065489

Positions:

chr1-196740644-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000186.4(CFH):c.2808G>T(p.Glu936Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,612,926 control chromosomes in the GnomAD database, including 29,128 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.15 ( 2412 hom., cov: 32)

Exomes 𝑓: 0.18 ( 26716 hom. )

Consequence

CFH
NM_000186.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -1.31

Variant links:

Genes affected

CFH (HGNC:4883): (complement factor H) This gene is a member of the Regulator of Complement Activation (RCA) gene cluster and encodes a protein with twenty short consensus repeat (SCR) domains. This protein is secreted into the bloodstream and has an essential role in the regulation of complement activation, restricting this innate defense mechanism to microbial infections. Mutations in this gene have been associated with hemolytic-uremic syndrome (HUS) and chronic hypocomplementemic nephropathy. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Oct 2011]

CFH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.9297004E-4).

BP6

Variant 1-196740644-G-T is Benign according to our data. Variant chr1-196740644-G-T is described in ClinVar as [Benign]. Clinvar id is 294509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-196740644-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFH	NM_000186.4 linkuse as main transcript	c.2808G>T	p.Glu936Asp	missense_variant	18/22	ENST00000367429.9	NP_000177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9 linkuse as main transcript	c.2808G>T	p.Glu936Asp	missense_variant	18/22	1	NM_000186.4	ENSP00000356399	P2

Frequencies

GnomAD3 genomes

AF:

0.154

AC:

23280

AN:

151646

Hom.:

2412

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0598

Gnomad AMI

AF:

0.257

Gnomad AMR

AF:

0.226

Gnomad ASJ

AF:

0.117

Gnomad EAS

AF:

0.480

Gnomad SAS

AF:

0.150

Gnomad FIN

AF:

0.145

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.171

Gnomad OTH

AF:

0.160

GnomAD3 exomes

AF:

0.205

AC:

51398

AN:

251208

Hom.:

7018

AF XY:

0.196

AC XY:

26649

AN XY:

135750

show subpopulations

Gnomad AFR exome

AF:

0.0572

Gnomad AMR exome

AF:

0.355

Gnomad ASJ exome

AF:

0.122

Gnomad EAS exome

AF:

0.504

Gnomad SAS exome

AF:

0.145

Gnomad FIN exome

AF:

0.140

Gnomad NFE exome

AF:

0.168

Gnomad OTH exome

AF:

0.195

GnomAD4 exome

AF:

0.178

AC:

260579

AN:

1461162

Hom.:

26716

Cov.:

AF XY:

0.176

AC XY:

128199

AN XY:

726902

show subpopulations

Gnomad4 AFR exome

AF:

0.0509

Gnomad4 AMR exome

AF:

0.336

Gnomad4 ASJ exome

AF:

0.121

Gnomad4 EAS exome

AF:

0.477

Gnomad4 SAS exome

AF:

0.142

Gnomad4 FIN exome

AF:

0.141

Gnomad4 NFE exome

AF:

0.171

Gnomad4 OTH exome

AF:

0.175

GnomAD4 genome

AF:

0.153

AC:

23273

AN:

151764

Hom.:

2412

Cov.:

AF XY:

0.154

AC XY:

11434

AN XY:

74128

show subpopulations

Gnomad4 AFR

AF:

0.0597

Gnomad4 AMR

AF:

0.226

Gnomad4 ASJ

AF:

0.117

Gnomad4 EAS

AF:

0.480

Gnomad4 SAS

AF:

0.150

Gnomad4 FIN

AF:

0.145

Gnomad4 NFE

AF:

0.171

Gnomad4 OTH

AF:

0.158

Alfa

AF:

0.167

Hom.:

4439

Bravo

AF:

0.161

TwinsUK

AF:

0.165

AC:

612

ALSPAC

AF:

0.170

AC:

656

ESP6500AA

AF:

0.0663

AC:

292

ESP6500EA

AF:

0.175

AC:

1503

ExAC

AF:

0.196

AC:

23731

Asia WGS

AF:

0.234

AC:

814

AN:

3478

EpiCase

AF:

0.172

EpiControl

AF:

0.175

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2020	This variant is associated with the following publications: (PMID: 31428128, 28173125, 14583443, 22790979, 20694013, 21868097, 18421087, 23660864, 25087612, 22718493) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hemolytic uremic syndrome, atypical, susceptibility to, 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Age related macular degeneration 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Basal laminar drusen

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Factor H deficiency;C0730295:Basal laminar drusen;C1853147:Age related macular degeneration 4;C2749604:Hemolytic uremic syndrome, atypical, susceptibility to, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 01, 2022

- -

Factor H deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.020

DANN

Uncertain

0.99

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.53

MetaRNN

Benign

0.00019

MetaSVM

Benign

-0.95

MutationTaster

Benign

1.0

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.89

REVEL

Benign

0.094

Sift

Benign

0.59

Sift4G

Benign

0.48

Vest4

0.067

MutPred

0.53

Loss of glycosylation at S938 (P = 0.1269);

MPC

0.20

ClinPred

0.0067

GERP RS

-2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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