rs114733570
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_002016.2(FLG):c.94G>T(p.Glu32*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,613,286 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00028 ( 0 hom. )
Consequence
FLG
NM_002016.2 stop_gained
NM_002016.2 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 2.76
Genes affected
FLG (HGNC:3748): (filaggrin) The protein encoded by this gene is an intermediate filament-associated protein that aggregates keratin intermediate filaments in mammalian epidermis. It is initially synthesized as a polyprotein precursor, profilaggrin (consisting of multiple filaggrin units of 324 aa each), which is localized in keratohyalin granules, and is subsequently proteolytically processed into individual functional filaggrin molecules. Mutations in this gene are associated with ichthyosis vulgaris.[provided by RefSeq, Dec 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 149 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-152315363-C-A is Pathogenic according to our data. Variant chr1-152315363-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 280469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-152315363-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FLG | NM_002016.2 | c.94G>T | p.Glu32* | stop_gained | 2/3 | ENST00000368799.2 | NP_002007.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FLG | ENST00000368799.2 | c.94G>T | p.Glu32* | stop_gained | 2/3 | 1 | NM_002016.2 | ENSP00000357789.1 |
Frequencies
GnomAD3 genomes 0.000204 AC: 31AN: 152060Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000123 AC: 31AN: 251144Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135750
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GnomAD4 exome AF: 0.000283 AC: 413AN: 1461108Hom.: 0 Cov.: 30 AF XY: 0.000259 AC XY: 188AN XY: 726884
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GnomAD4 genome 0.000204 AC: 31AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74396
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ichthyosis vulgaris Pathogenic:5
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 06, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 13, 2024 | Criteria applied: PVS1,PM2,PM3 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | May 15, 2023 | PVS1, PM2 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Jun 05, 2017 | This c.94G>T (p.Glu32*) variant in the FLG gene has been reported in ClinVar (SCV000330388.2) and has been observed in 5 heterozygous individuals in the ExAC database (http://exac.broadinstitute.org/variant/1-152287839-C-A). This c.94G>T creates a stop codon at amino acid position 32 of the FLG gene (p.Glu32*), which is predicted to disrupt the function of the protein. Loss of function variants are disease-causing but the disorder is considered semidominant. Thus, heterozygous individuals may show a mild phenotype with incomplete penetrance. It is thus interpreted as a pathogenic variant with incomplete penetrance. - |
FLG-related disorder Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 23, 2020 | The FLG c.94G>T (p.Glu32Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is reported at a frequency of 0.000264 in the European (non-Finnish) population of the Genome Aggregation Database. This allele frequency is high but is consistent with reduced penetrance and disease prevalence estimates. Based on the potential impact of truncating variants and application of ACMG criteria, the p.Glu32Ter variant is classified as likely pathogenic for FLG-related disorders. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 05, 2023 | The FLG c.94G>T variant is predicted to result in premature protein termination (p.Glu32*). This variant has been reported in the compound heterozygous state in an individual with an asthma/eczema phenotypes in addition to neurological features unrelated to FLG (Patient 10a, Table S2, Torti et al. 2019. PubMed ID: 30739909; Furthermore, loss of function variants in FLG are expected to be pathogenic (Smith et al. 2006. PubMed ID: 16444271; Kawasaki et al. 2012. PubMed ID: 22409988). This variant is reported in 0.026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in FLG are expected to be pathogenic. This variant is interpreted as likely pathogenic. - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 21, 2019 | This sequence change results in a premature translational stop signal in the FLG gene (p.Glu32*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 4030 amino acids (>99%) of the FLG protein. This variant is present in population databases (rs114733570, ExAC 0.03%). This variant has not been reported in the literature in individuals with FLG-related disease. ClinVar contains an entry for this variant (Variation ID: 280469). Loss-of-function variants in FLG are known to be pathogenic (PMID: 16444271, 22409988). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 09, 2022 | Nonsense variant predicted to result in protein truncation, as the last 4030 amino acids are lost, and many other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 30739909, 31589614, 32018027, 31447099) - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
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