chr1-196740686-G-T

Position:

chr1-196740686-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PS1_ModerateBP4_StrongBS1BS2

The NM_000186.4(CFH):c.2850G>T(p.Gln950His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00463 in 1,613,902 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Synonymous variant affecting the same amino acid position (i.e. Q950Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 25 hom. )

Consequence

CFH
NM_000186.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:10

Conservation

PhyloP100: -0.600

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:

ENSG00000289697 (HGNC:):

ENSG00000289697 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PS1

Transcript NM_000186.4 (CFH) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

BP4

Computational evidence support a benign effect (MetaRNN=0.037262112).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00399 (607/152148) while in subpopulation NFE AF= 0.0061 (415/68018). AF 95% confidence interval is 0.00562. There are 0 homozygotes in gnomad4. There are 274 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 25 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFH	NM_000186.4 linkuse as main transcript	c.2850G>T	p.Gln950His	missense_variant	18/22	ENST00000367429.9	NP_000177.2	P08603A0A024R962

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9 linkuse as main transcript	c.2850G>T	p.Gln950His	missense_variant	18/22	1	NM_000186.4	ENSP00000356399.4		P08603
ENSG00000289697	ENST00000696032.1 linkuse as main transcript	c.2850G>T	p.Gln950His	missense_variant	18/27			ENSP00000512341.1		A0A8Q3SIA1

Frequencies

GnomAD3 genomes

AF:

0.00399

AC:

607

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00114

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00387

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00161

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00610

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00394

AC:

990

AN:

251400

Hom.:

AF XY:

0.00383

AC XY:

520

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00185

Gnomad ASJ exome

AF:

0.0172

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00139

Gnomad NFE exome

AF:

0.00598

Gnomad OTH exome

AF:

0.00424

GnomAD4 exome

AF:

0.00469

AC:

6862

AN:

1461754

Hom.:

Cov.:

AF XY:

0.00460

AC XY:

3342

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.00102

Gnomad4 AMR exome

AF:

0.00215

Gnomad4 ASJ exome

AF:

0.0167

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.00167

Gnomad4 NFE exome

AF:

0.00527

Gnomad4 OTH exome

AF:

0.00532

GnomAD4 genome

AF:

0.00399

AC:

607

AN:

152148

Hom.:

Cov.:

AF XY:

0.00369

AC XY:

274

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.00386

Gnomad4 ASJ

AF:

0.0170

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00161

Gnomad4 NFE

AF:

0.00610

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00570

Hom.:

Bravo

AF:

0.00422

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00616

AC:

ExAC

AF:

0.00358

AC:

435

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00507

EpiControl

AF:

0.00433

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	CFH: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2020	Reported in multiple individuals with atypical hemolytic uremic syndrome or age-related macular degeneration (Neumann et al., 2003; Caprioli et al., 2003; Maga et al., 2010; Sartz et al., 2012; van de Ven et al., 2013; Duvvari et al., 2016; Szarvas et al., 2016; Besbas et al., 2017; Seaby et al., 2017; Fidalgo et al., 2017; Gaut et al., 2017; Geerlings et al., 2018); Functional studies demonstrated moderately decreased cofactor function of factor H and somewhat decreased expression, but normal complement inhibitory function in fluid phase (Mohlin et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32424742, 31118930, 31865800, 30870849, 26826462, 23251215, 25733390, 29888403, 30046676, 30377230, 28589114, 29148534, 28056875, 26346198, 27007659, 23685748, 12960213, 22250080, 23660864, 18557729, 28752844, 20513133, 14583443) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 12, 2018	- -

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II

Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hemolytic uremic syndrome, atypical, susceptibility to, 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Atypical hemolytic-uremic syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 04, 2021

- -

Age related macular degeneration 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Basal laminar drusen

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.92

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.50

M_CAP

Benign

0.061

MetaRNN

Benign

0.037

MetaSVM

Benign

-0.93

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.32

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.019

Vest4

0.90

MutPred

0.80

Gain of disorder (P = 0.1052);

MVP

0.95

MPC

0.58

ClinPred

0.031

GERP RS

-4.9

gMVP

0.69

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