1-196690107-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_000186.4(CFH):c.1204C>T(p.His402Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 1,610,204 control chromosomes in the GnomAD database, including 330,962 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.64 ( 31992 hom., cov: 31)

Exomes 𝑓: 0.64 ( 298970 hom. )

Consequence

CFH
NM_000186.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: -8.33

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.2569295E-6).

BP6

Variant 1-196690107-C-T is Benign according to our data. Variant chr1-196690107-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 294490.We mark this variant Likely_benign, oryginal submissions are: {Benign=12, Uncertain_significance=1}. Variant chr1-196690107-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4 link	c.1204C>T	p.His402Tyr	missense_variant	Exon 9 of 22	ENST00000367429.9	NP_000177.2	P08603A0A024R962
CFH	NM_001014975.3 link	c.1204C>T	p.His402Tyr	missense_variant	Exon 9 of 10		NP_001014975.1	A0A0D9SG88

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9 link	c.1204C>T	p.His402Tyr	missense_variant	Exon 9 of 22	1	NM_000186.4	ENSP00000356399.4		P08603
ENSG00000289697	ENST00000696032.1 link	c.1204C>T	p.His402Tyr	missense_variant	Exon 9 of 27			ENSP00000512341.1		A0A8Q3SIA1

Frequencies

GnomAD3 genomes

AF:

0.645

AC:

97836

AN:

151784

Hom.:

31967

Cov.:

show subpopulations

Gnomad AFR

AF:

0.629

Gnomad AMI

AF:

0.519

Gnomad AMR

AF:

0.737

Gnomad ASJ

AF:

0.661

Gnomad EAS

AF:

0.948

Gnomad SAS

AF:

0.719

Gnomad FIN

AF:

0.563

Gnomad MID

AF:

0.663

Gnomad NFE

AF:

0.618

Gnomad OTH

AF:

0.665

GnomAD3 exomes

AF:

0.680

AC:

169954

AN:

250026

Hom.:

59360

AF XY:

0.673

AC XY:

90974

AN XY:

135116

show subpopulations

Gnomad AFR exome

AF:

0.627

Gnomad AMR exome

AF:

0.834

Gnomad ASJ exome

AF:

0.666

Gnomad EAS exome

AF:

0.954

Gnomad SAS exome

AF:

0.698

Gnomad FIN exome

AF:

0.563

Gnomad NFE exome

AF:

0.616

Gnomad OTH exome

AF:

0.660

GnomAD4 exome

AF:

0.636

AC:

927619

AN:

1458302

Hom.:

298970

Cov.:

AF XY:

0.637

AC XY:

462112

AN XY:

725588

show subpopulations

Gnomad4 AFR exome

AF:

0.630

Gnomad4 AMR exome

AF:

0.824

Gnomad4 ASJ exome

AF:

0.654

Gnomad4 EAS exome

AF:

0.940

Gnomad4 SAS exome

AF:

0.694

Gnomad4 FIN exome

AF:

0.559

Gnomad4 NFE exome

AF:

0.616

Gnomad4 OTH exome

AF:

0.644

GnomAD4 genome

AF:

0.645

AC:

97903

AN:

151902

Hom.:

31992

Cov.:

AF XY:

0.647

AC XY:

48054

AN XY:

74232

show subpopulations

Gnomad4 AFR

AF:

0.629

Gnomad4 AMR

AF:

0.738

Gnomad4 ASJ

AF:

0.661

Gnomad4 EAS

AF:

0.949

Gnomad4 SAS

AF:

0.720

Gnomad4 FIN

AF:

0.563

Gnomad4 NFE

AF:

0.618

Gnomad4 OTH

AF:

0.664

Alfa

AF:

0.626

Hom.:

13228

Bravo

AF:

0.660

TwinsUK

AF:

0.612

AC:

2270

ALSPAC

AF:

0.622

AC:

2398

ESP6500AA

AF:

0.637

AC:

2808

ESP6500EA

AF:

0.618

AC:

5312

ExAC

AF:

0.671

AC:

81367

Asia WGS

AF:

0.781

AC:

2716

AN:

3478

EpiCase

AF:

0.632

EpiControl

AF:

0.628

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Mar 09, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26895476, 23497844, 28173125, 29686068, 26376595, 15761120, 20038862, 22875704, 19823576, 20869121, 20378180, 20132989, 22277662, 22552255, 16936732, 24036949, 20581873, 23112567, 22933840, 22509112, 20664795, 18604638, 19399715, 22456601, 24550392, 20660596, 21784901, 21930971, 17339482, 20688737, 20574013, 20538999, 20042647, 18263814, 22388616, 21649859, 17464302, 19000922, 17869048, 19187590, 22197220, 20708732, 22965593, 21825189, 18163432, 25087612) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hemolytic uremic syndrome, atypical, susceptibility to, 1

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Basal laminar drusen

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Age related macular degeneration 4

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Factor H deficiency

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Atypical hemolytic-uremic syndrome

Benign:1

Oct 05, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.0010

DANN

Benign

0.22

DEOGEN2

Benign

0.0033

.;T;.

Eigen

Benign

-2.8

Eigen_PC

Benign

-2.9

FATHMM_MKL

Benign

0.00085

LIST_S2

Benign

0.13

T;T;T

MetaRNN

Benign

0.0000043

T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.25

PROVEAN

Benign

0.010

N;.;N

REVEL

Benign

0.086

Sift

Benign

1.0

T;.;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.087

MPC

0.16

ClinPred

0.023

GERP RS

-9.1

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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