chr6-109760253-C-T
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_014845.6(FIG4):c.1141C>T(p.Arg381*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,612,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
FIG4
NM_014845.6 stop_gained
NM_014845.6 stop_gained
Scores
2
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3
Clinical Significance
Conservation
PhyloP100: 3.18
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 6-109760253-C-T is Pathogenic according to our data. Variant chr6-109760253-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 217228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-109760253-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152034Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251254Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135786
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GnomAD4 exome AF: 0.0000157 AC: 23AN: 1460650Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 13AN XY: 726662
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GnomAD4 genome AF: 0.0000789 AC: 12AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74390
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 22, 2023 | PP4, PM3, PVS1 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 04, 2024 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 23623387, Umair2021[Case Report], 21705420, 32268254) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2019 | - - |
Charcot-Marie-Tooth disease type 4J Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Mar 29, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 16, 2014 | - - |
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium Ii, University Of Miami | Jan 06, 2016 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 23, 2019 | The p.R381* pathogenic mutation (also known as c.1141C>T), located in coding exon 11 of the FIG4 gene, results from a C to T substitution at nucleotide position 1141. This changes the amino acid from an arginine to a stop codon within coding exon 11. The p.R381* alteration was previously reported in a compound heterozygous state with the p.I41T alteration in an 11 year old female patient with Charcot-Marie-Tooth disease type 4J (CMT4J) (Nicholson G et al. Brain, 2011 Jul;134:1959-71). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
FIG4-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 08, 2023 | The FIG4 c.1141C>T variant is predicted to result in premature protein termination (p.Arg381*). This variant was reported in the compound heterozygous state in one individual with Charcot-Marie-Tooth disease type 4J (Nicholson et al. 2011. PubMed ID: 21705420; Zimmermann et al. 2020. PubMed ID: 32268254). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD. Nonsense variants in FIG4 are expected to be pathogenic. This variant is interpreted as likely pathogenic. - |
Charcot-Marie-Tooth disease type 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 13, 2025 | This sequence change creates a premature translational stop signal (p.Arg381*) 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 (rs377357931, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 21705420). ClinVar contains an entry for this variant (Variation ID: 217228). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at