rs800292

Positions:

chr1-196673103-G-A

Variant summary

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

The NM_000186.4(CFH):c.184G>A(p.Val62Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 1,612,358 control chromosomes in the GnomAD database, including 70,983 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 0.40 ( 15198 hom., cov: 31)

Exomes 𝑓: 0.26 ( 55785 hom. )

Consequence

CFH
NM_000186.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13O:2

Conservation

PhyloP100: 1.60

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=5.604542E-6).

BP6

Variant 1-196673103-G-A is Benign according to our data. Variant chr1-196673103-G-A is described in ClinVar as [Benign]. Clinvar id is 16550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-196673103-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.709 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.184G>A	p.Val62Ile	missense_variant	2/22	ENST00000367429.9	NP_000177.2
CFH	NM_001014975.3 linkuse as main transcript	c.184G>A	p.Val62Ile	missense_variant	2/10		NP_001014975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9 linkuse as main transcript	c.184G>A	p.Val62Ile	missense_variant	2/22	1	NM_000186.4	ENSP00000356399	P2

Frequencies

GnomAD3 genomes

AF:

0.397

AC:

60251

AN:

151828

Hom.:

15151

Cov.:

show subpopulations

Gnomad AFR

AF:

0.716

Gnomad AMI

AF:

0.294

Gnomad AMR

AF:

0.388

Gnomad ASJ

AF:

0.270

Gnomad EAS

AF:

0.423

Gnomad SAS

AF:

0.326

Gnomad FIN

AF:

0.296

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.234

Gnomad OTH

AF:

0.357

GnomAD3 exomes

AF:

0.317

AC:

79518

AN:

250544

Hom.:

14648

AF XY:

0.305

AC XY:

41348

AN XY:

135430

show subpopulations

Gnomad AFR exome

AF:

0.725

Gnomad AMR exome

AF:

0.375

Gnomad ASJ exome

AF:

0.269

Gnomad EAS exome

AF:

0.421

Gnomad SAS exome

AF:

0.314

Gnomad FIN exome

AF:

0.302

Gnomad NFE exome

AF:

0.235

Gnomad OTH exome

AF:

0.271

GnomAD4 exome

AF:

0.261

AC:

381288

AN:

1460412

Hom.:

55785

Cov.:

AF XY:

0.261

AC XY:

189294

AN XY:

726594

show subpopulations

Gnomad4 AFR exome

AF:

0.734

Gnomad4 AMR exome

AF:

0.381

Gnomad4 ASJ exome

AF:

0.264

Gnomad4 EAS exome

AF:

0.415

Gnomad4 SAS exome

AF:

0.314

Gnomad4 FIN exome

AF:

0.296

Gnomad4 NFE exome

AF:

0.230

Gnomad4 OTH exome

AF:

0.282

GnomAD4 genome

AF:

0.397

AC:

60366

AN:

151946

Hom.:

15198

Cov.:

AF XY:

0.399

AC XY:

29600

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.716

Gnomad4 AMR

AF:

0.389

Gnomad4 ASJ

AF:

0.270

Gnomad4 EAS

AF:

0.423

Gnomad4 SAS

AF:

0.326

Gnomad4 FIN

AF:

0.296

Gnomad4 NFE

AF:

0.234

Gnomad4 OTH

AF:

0.357

Alfa

AF:

0.253

Hom.:

14695

Bravo

AF:

0.417

TwinsUK

AF:

0.234

AC:

866

ALSPAC

AF:

0.226

AC:

872

ESP6500AA

AF:

0.708

AC:

3119

ESP6500EA

AF:

0.222

AC:

1909

ExAC

AF:

0.320

AC:

38882

Asia WGS

AF:

0.432

AC:

1502

AN:

3478

EpiCase

AF:

0.227

EpiControl

AF:

0.231

ClinVar

Significance: Benign

Submissions summary: Benign:13Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

not provided, no classification provided	not provided	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 21106043, 25087612, 20538655, 23274582, 18340363, 19549636, 18421087, 20574013, 24722444, 21270465, 24550392, 22509112, 23441108, 20132989, 19187823, 21397333, 21555552, 16299065, 29686068, 28173125) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Basal laminar drusen

Benign:3

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	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Age related macular degeneration 4

Benign:2Other:1

risk factor, no assertion criteria provided	literature only	OMIM	Sep 11, 2011	- -
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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

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	- -

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

0.059

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.087

DEOGEN2

Benign

0.0040

.;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0021

LIST_S2

Benign

0.36

T;T;T

MetaRNN

Benign

0.0000056

T;T;T

MetaSVM

Benign

-0.94

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.49

N;.;N

REVEL

Benign

0.14

Sift

Benign

1.0

T;.;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.10

MPC

0.11

ClinPred

0.0013

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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