rs535554973
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_014845.6(FIG4):c.1313A>G(p.Glu438Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,796 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E438K) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
FIG4
NM_014845.6 missense
NM_014845.6 missense
Scores
2
12
5
Clinical Significance
Conservation
PhyloP100: 7.09
Genes affected
FIG4 (HGNC:16873): (FIG4 phosphoinositide 5-phosphatase) The protein encoded by this gene belongs to the SAC domain-containing protein gene family. The SAC domain, approximately 400 amino acids in length and consisting of seven conserved motifs, has been shown to possess phosphoinositide phosphatase activity. The yeast homolog, Sac1p, is involved in the regulation of various phosphoinositides, and affects diverse cellular functions such as actin cytoskeleton organization, Golgi function, and maintenance of vacuole morphology. Membrane-bound phosphoinositides function as signaling molecules and play a key role in vesicle trafficking in eukaryotic cells. Mutations in this gene have been associated with Charcot-Marie-Tooth disease, type 4J. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FIG4 | NM_014845.6 | c.1313A>G | p.Glu438Gly | missense_variant | 12/23 | ENST00000230124.8 | |
FIG4 | XM_011536281.4 | c.1250A>G | p.Glu417Gly | missense_variant | 12/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FIG4 | ENST00000230124.8 | c.1313A>G | p.Glu438Gly | missense_variant | 12/23 | 1 | NM_014845.6 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152218Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251368Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135864
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461460Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6AN XY: 727086
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GnomAD4 genome ? AF: 0.00000656 AC: 1AN: 152336Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74502
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 11, 2020 | The p.E438G variant (also known as c.1313A>G), located in coding exon 12 of the FIG4 gene, results from an A to G substitution at nucleotide position 1313. The glutamic acid at codon 438 is replaced by glycine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Charcot-Marie-Tooth disease type 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 28, 2018 | 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with FIG4-related disease. This variant is present in population databases (rs535554973, ExAC 0.02%). This sequence change replaces glutamic acid with glycine at codon 438 of the FIG4 protein (p.Glu438Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MutPred
Gain of catalytic residue at A437 (P = 0.0233);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
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