Variant rs121913056 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1_ModeratePM2PP3_StrongPP5

The NM_000186.4(CFH):c.1291T>A(p.Cys431Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CFH
NM_000186.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.21

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PS1

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

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 1-196690194-T-A is Pathogenic according to our data. Variant chr1-196690194-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 16551.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFH	NM_000186.4 linkuse as main transcript	c.1291T>A	p.Cys431Ser	missense_variant	9/22	ENST00000367429.9	NP_000177.2	P08603A0A024R962
CFH	NM_001014975.3 linkuse as main transcript	c.1291T>A	p.Cys431Ser	missense_variant	9/10		NP_001014975.1	A0A0D9SG88

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9 linkuse as main transcript	c.1291T>A	p.Cys431Ser	missense_variant	9/22	1	NM_000186.4	ENSP00000356399.4		P08603
ENSG00000289697	ENST00000696032.1 linkuse as main transcript	c.1291T>A	p.Cys431Ser	missense_variant	9/27			ENSP00000512341.1		A0A8Q3SIA1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250938

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135592

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461238

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726924

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Factor H deficiency

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.54

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

.;T;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-7.8

D;.;D

REVEL

Pathogenic

0.80

Sift

Uncertain

0.014

D;.;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

0.99

.;.;D

Vest4

0.84

MutPred

0.99

Gain of disorder (P = 0.0022);Gain of disorder (P = 0.0022);.;

MVP

1.0

MPC

0.69

ClinPred

0.99

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.96

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