rs1060501903
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001370298.3(FGD4):āc.1657A>Gā(p.Ile553Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,116 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 Uncertain significance (ā ).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 33)
Exomes š: 0.0000082 ( 0 hom. )
Consequence
FGD4
NM_001370298.3 missense
NM_001370298.3 missense
Scores
1
9
8
Clinical Significance
Conservation
PhyloP100: 9.09
Genes affected
FGD4 (HGNC:19125): (FYVE, RhoGEF and PH domain containing 4) This gene encodes a protein that is involved in the regulation of the actin cytoskeleton and cell shape. This protein contains an actin filament-binding domain, which together with its Dbl homology domain and one of its pleckstrin homology domains, can form microspikes. This protein can activate MAPK8 independently of the actin filament-binding domain, and it is also involved in the activation of CDC42 via the exchange of bound GDP for free GTP. The activation of CDC42 also enables this protein to play a role in mediating the cellular invasion of Cryptosporidium parvum, an intracellular parasite that infects the gastrointestinal tract. Mutations in this gene can cause Charcot-Marie-Tooth disease type 4H (CMT4H), a disorder of the peripheral nervous system. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2015]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.25260165).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGD4 | NM_001370298.3 | c.1657A>G | p.Ile553Val | missense_variant | 10/17 | ENST00000534526.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGD4 | ENST00000534526.7 | c.1657A>G | p.Ile553Val | missense_variant | 10/17 | 5 | NM_001370298.3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152262Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251452Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135904
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461854Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727234
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152262Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74406
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease type 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 28, 2018 | In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This sequence change replaces isoleucine with valine at codon 416 of the FGD4 protein (p.Ile416Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FGD4-related disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N
REVEL
Uncertain
Sift
Benign
D;T;T;T;T
Sift4G
Benign
T;T;T;T;T
Polyphen
0.41, 0.65
.;B;P;.;B
Vest4
MutPred
0.37
.;.;.;.;Gain of disorder (P = 0.1765);
MVP
MPC
0.34
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at