GeneBe

1-196652163-TG-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000186.4(CFH):​c.47delG​(p.Cys16LeufsTer2) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000685 in 1,459,092 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CFH
NM_000186.4 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.46

Publications

0 publications found
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 Gene-Disease associations (from GenCC):
  • primary membranoproliferative glomerulonephritis
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • atypical hemolytic-uremic syndrome
    Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
  • hemolytic uremic syndrome, atypical, susceptibility to, 1
    Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
  • complement factor H deficiency
    Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
  • basal laminar drusen
    Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
  • Doyne honeycomb retinal dystrophy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • dense deposit disease
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 79 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-196652163-TG-T is Pathogenic according to our data. Variant chr1-196652163-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1712461.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CFHNM_000186.4 linkc.47delG p.Cys16LeufsTer2 frameshift_variant Exon 1 of 22 ENST00000367429.9 NP_000177.2 P08603A0A024R962
CFHNM_001014975.3 linkc.47delG p.Cys16LeufsTer2 frameshift_variant Exon 1 of 10 NP_001014975.1 A0A0D9SG88

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CFHENST00000367429.9 linkc.47delG p.Cys16LeufsTer2 frameshift_variant Exon 1 of 22 1 NM_000186.4 ENSP00000356399.4 P08603
ENSG00000289697ENST00000696032.1 linkc.47delG p.Cys16LeufsTer2 frameshift_variant Exon 1 of 27 ENSP00000512341.1 A0A8Q3SIA1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459092
Hom.:
0
Cov.:
28
AF XY:
0.00000138
AC XY:
1
AN XY:
726030
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33422
American (AMR)
AF:
0.00
AC:
0
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26110
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39652
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86208
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53348
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5758
European-Non Finnish (NFE)
AF:
9.01e-7
AC:
1
AN:
1109562
Other (OTH)
AF:
0.00
AC:
0
AN:
60316
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Atypical hemolytic-uremic syndrome Pathogenic:1
Feb 28, 2022
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
4.5
Mutation Taster
=15/185
disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs1354648948; hg19: chr1-196621293; API