rs772320287
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_014845.6(FIG4):c.1666dup(p.Thr556AsnfsTer21) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000124 in 1,613,798 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
FIG4
NM_014845.6 frameshift
NM_014845.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.97
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 Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 6-109766807-G-GA is Pathogenic according to our data. Variant chr6-109766807-G-GA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 355040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FIG4 | NM_014845.6 | c.1666dup | p.Thr556AsnfsTer21 | frameshift_variant | 15/23 | ENST00000230124.8 | |
FIG4 | XM_011536281.4 | c.1603dup | p.Thr535AsnfsTer21 | frameshift_variant | 15/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FIG4 | ENST00000230124.8 | c.1666dup | p.Thr556AsnfsTer21 | frameshift_variant | 15/23 | 1 | NM_014845.6 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152078Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251434Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135890
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GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461720Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727180
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 152078Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74286
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 16, 2019 | The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. - |
FIG4-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | The c.1666dup (p.Thr556AsnfsTer20) results in a frameshift, and is predicted to result in premature termination of the protein. The p.Thr556AsnfsTer20 variant has been reported in one study in two patients with Charcot-Marie-Tooth disease in a compound heterozygous state with a missense variant (Nicholson et al. 2011). No publications were found for this variant in relation to autosomal dominant amyotrophic lateral sclerosis. The p.Thr556AsnfsTer20 variant was absent from 206 controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Due to the potential impact of frameshift variants, the p.Thr556AsnfsTer20 variant is classified as likely pathogenic for FIG4-related disorders. - |
Charcot-Marie-Tooth disease type 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | This sequence change creates a premature translational stop signal (p.Thr556Asnfs*21) in the FIG4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FIG4 are known to be pathogenic (PMID: 23623387, 30740813). This variant is present in population databases (rs772320287, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with autosomal recessive Charcot-Marie-Tooth disease (PMID: 21705420). ClinVar contains an entry for this variant (Variation ID: 355040). For these reasons, this variant has been classified as Pathogenic. - |
Charcot-Marie-Tooth disease type 4J Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium Ii, University Of Miami | Jan 06, 2016 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at