rs764799053
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_014845.6(FIG4):βc.2095C>Tβ(p.Arg699Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,613,594 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (β β ).
Frequency
Genomes: π 0.000033 ( 0 hom., cov: 32)
Exomes π: 0.000047 ( 0 hom. )
Consequence
FIG4
NM_014845.6 missense, splice_region
NM_014845.6 missense, splice_region
Scores
6
9
4
Splicing: ADA: 0.9975
2
Clinical Significance
Conservation
PhyloP100: 1.70
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FIG4 | NM_014845.6 | c.2095C>T | p.Arg699Cys | missense_variant, splice_region_variant | Exon 18 of 23 | ENST00000230124.8 | NP_055660.1 | |
FIG4 | XM_011536281.4 | c.2032C>T | p.Arg678Cys | missense_variant, splice_region_variant | Exon 18 of 23 | XP_011534583.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152112Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251364Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135852
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GnomAD4 exome AF: 0.0000472 AC: 69AN: 1461482Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 38AN XY: 727066
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 152112Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74308
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Yunis-Varon syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Oct 30, 2018 | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 28, 2016 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 05, 2023 | The c.2095C>T (p.R699C) alteration is located in exon 18 (coding exon 18) of the FIG4 gene. This alteration results from a C to T substitution at nucleotide position 2095, causing the arginine (R) at amino acid position 699 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
FIG4-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 05, 2024 | The FIG4 c.2095C>T variant is predicted to result in the amino acid substitution p.Arg699Cys. This variant has been reported in two individuals with amyotrophic lateral sclerosis (MΓΌller et al. 2018. PubMed ID: 29650794; Table S2, Tripolszki et al. 2019. PubMed ID: 31475037). However, it has also been reported in a control cohort (Table S2, Tripolszki et al. 2019. PubMed ID: 31475037). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Charcot-Marie-Tooth disease type 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 13, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 699 of the FIG4 protein (p.Arg699Cys). This variant is present in population databases (rs764799053, gnomAD 0.007%). This missense change has been observed in individual(s) with amyotropic lateral sclerosis (PMID: 29650794, 31475037). ClinVar contains an entry for this variant (Variation ID: 407085). 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. 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
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Loss of disorder (P = 0.0416);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at