4-109746417-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP6

The NM_000204.5(CFI):​c.1234G>A​(p.Val412Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V412E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

CFI
NM_000204.5 missense

Scores

3
8
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3O:1

Conservation

PhyloP100: 1.24
Variant links:
Genes affected
CFI (HGNC:5394): (complement factor I) This gene encodes a serine proteinase that is essential for regulating the complement cascade. The encoded preproprotein is cleaved to produce both heavy and light chains, which are linked by disulfide bonds to form a heterodimeric glycoprotein. This heterodimer can cleave and inactivate the complement components C4b and C3b, and it prevents the assembly of the C3 and C5 convertase enzymes. Defects in this gene cause complement factor I deficiency, an autosomal recessive disease associated with a susceptibility to pyogenic infections. Mutations in this gene have been associated with a predisposition to atypical hemolytic uremic syndrome, a disease characterized by acute renal failure, microangiopathic hemolytic anemia and thrombocytopenia. Primary glomerulonephritis with immune deposits and age-related macular degeneration are other conditions associated with mutations of this gene. [provided by RefSeq, Dec 2015]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.41706142).
BP6
Variant 4-109746417-C-T is Benign according to our data. Variant chr4-109746417-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 217862.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CFINM_000204.5 linkc.1234G>A p.Val412Met missense_variant Exon 11 of 13 ENST00000394634.7 NP_000195.3 P05156A8K3L0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CFIENST00000394634.7 linkc.1234G>A p.Val412Met missense_variant Exon 11 of 13 1 NM_000204.5 ENSP00000378130.2 P05156
ENSG00000285330ENST00000645635.1 linkc.1234G>A p.Val412Met missense_variant Exon 11 of 15 ENSP00000493607.1 A0A2R8Y3M9

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152020
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000386
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000915
AC:
23
AN:
251316
Hom.:
0
AF XY:
0.0000589
AC XY:
8
AN XY:
135818
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000869
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000707
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.000327
GnomAD4 exome
AF:
0.0000294
AC:
43
AN:
1461706
Hom.:
0
Cov.:
32
AF XY:
0.0000344
AC XY:
25
AN XY:
727176
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000302
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152138
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74392
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000387
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000278
Hom.:
0
Bravo
AF:
0.0000113
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000107
AC:
13
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Atypical hemolytic-uremic syndrome with I factor anomaly;C3463916:Factor I deficiency;C3809523:Age related macular degeneration 13 Uncertain:1
Feb 21, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1
Oct 11, 2023
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Age related macular degeneration 13 Benign:1
Oct 13, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant (GRCh38; NM_000204.5:c.1234G>A:p.Val412Met) results in a missense mutation with the conversion of Valine (Nonpolar amino acid) to Methionine (Nonpolar amino acid) in the CFI protein. Not observed at significant frequency in large population cohorts (gnomAD). Multiple lines of computational evidence of this variant suggest no impact on gene or gene product. Reputable source recently reports variant as benign. This variant is associated with the following publications: PubMed: 25986072, 31635417 Based on conflicting evidence or insufficient data to determine whether the variant is benign or pathogenic, the clinical significance of this alteration remains unclear. In summary, this variant meets our criteria for classification as of Unknown Clinical Significance based on the evidence outlined. -

not provided Benign:1
Jan 27, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Macular degeneration, age-related, 13, susceptibility to Other:1
Jul 01, 2015
OMIM
Significance: risk factor
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.67
BayesDel_addAF
Benign
-0.089
T
BayesDel_noAF
Uncertain
0.0
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.64
.;D;D;.
Eigen
Uncertain
0.34
Eigen_PC
Benign
0.10
FATHMM_MKL
Benign
0.26
N
LIST_S2
Benign
0.82
T;T;T;T
M_CAP
Pathogenic
0.69
D
MetaRNN
Benign
0.42
T;T;T;T
MetaSVM
Uncertain
0.76
D
MutationAssessor
Pathogenic
3.1
.;M;.;.
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-2.0
.;N;N;N
REVEL
Uncertain
0.49
Sift
Uncertain
0.0050
.;D;D;D
Sift4G
Uncertain
0.0080
.;D;D;D
Polyphen
1.0, 0.99, 0.99
.;D;D;D
Vest4
0.69, 0.83, 0.79
MVP
0.85
MPC
0.40
ClinPred
0.20
T
GERP RS
5.6
Varity_R
0.36
gMVP
0.86

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.

Other links and lift over

dbSNP: rs371432629; hg19: chr4-110667573; COSMIC: COSV67100291; COSMIC: COSV67100291; API