rs2274700

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000186.4(CFH):c.1419G>A(p.Ala473=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 1,610,552 control chromosomes in the GnomAD database, including 145,615 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 14793 hom., cov: 31)

Exomes 𝑓: 0.42 ( 130822 hom. )

Consequence

CFH
NM_000186.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.485

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 1-196713817-G-A is Benign according to our data. Variant chr1-196713817-G-A is described in ClinVar as [Benign]. Clinvar id is 294491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-196713817-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.485 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.541 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.1419G>A	p.Ala473=	synonymous_variant	10/22	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.1419G>A	p.Ala473=	synonymous_variant	10/22	1	NM_000186.4	ENSP00000356399	P2

Frequencies

GnomAD3 genomes

AF:

0.439

AC:

66624

AN:

151640

Hom.:

14776

Cov.:

show subpopulations

Gnomad AFR

AF:

0.465

Gnomad AMI

AF:

0.258

Gnomad AMR

AF:

0.485

Gnomad ASJ

AF:

0.522

Gnomad EAS

AF:

0.444

Gnomad SAS

AF:

0.558

Gnomad FIN

AF:

0.401

Gnomad MID

AF:

0.456

Gnomad NFE

AF:

0.408

Gnomad OTH

AF:

0.470

GnomAD3 exomes

AF:

0.444

AC:

111026

AN:

250332

Hom.:

25005

AF XY:

0.448

AC XY:

60592

AN XY:

135286

show subpopulations

Gnomad AFR exome

AF:

0.462

Gnomad AMR exome

AF:

0.459

Gnomad ASJ exome

AF:

0.521

Gnomad EAS exome

AF:

0.431

Gnomad SAS exome

AF:

0.546

Gnomad FIN exome

AF:

0.403

Gnomad NFE exome

AF:

0.412

Gnomad OTH exome

AF:

0.430

GnomAD4 exome

AF:

0.420

AC:

613118

AN:

1458796

Hom.:

130822

Cov.:

AF XY:

0.424

AC XY:

308017

AN XY:

725824

show subpopulations

Gnomad4 AFR exome

AF:

0.471

Gnomad4 AMR exome

AF:

0.466

Gnomad4 ASJ exome

AF:

0.509

Gnomad4 EAS exome

AF:

0.442

Gnomad4 SAS exome

AF:

0.545

Gnomad4 FIN exome

AF:

0.397

Gnomad4 NFE exome

AF:

0.405

Gnomad4 OTH exome

AF:

0.427

GnomAD4 genome

AF:

0.439

AC:

66678

AN:

151756

Hom.:

14793

Cov.:

AF XY:

0.446

AC XY:

33037

AN XY:

74146

show subpopulations

Gnomad4 AFR

AF:

0.465

Gnomad4 AMR

AF:

0.485

Gnomad4 ASJ

AF:

0.522

Gnomad4 EAS

AF:

0.444

Gnomad4 SAS

AF:

0.559

Gnomad4 FIN

AF:

0.401

Gnomad4 NFE

AF:

0.408

Gnomad4 OTH

AF:

0.472

Alfa

AF:

0.382

Hom.:

11061

Bravo

AF:

0.442

Asia WGS

AF:

0.525

AC:

1823

AN:

3474

EpiCase

AF:

0.426

EpiControl

AF:

0.419

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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: 25087612, 21868097, 22848687, 16299065) -

Hemolytic uremic syndrome, atypical, susceptibility to, 1

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. -

Age related macular degeneration 4

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. -

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

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). 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. -

Atypical hemolytic-uremic syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 05, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

3.7

DANN

Benign

0.15

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