rs397507563
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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):βc.3702delβ(p.Ser1235HisfsTer211) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000269 in 1,612,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ).
Frequency
Genomes: π 0.00015 ( 0 hom., cov: 30)
Exomes π: 0.00028 ( 0 hom. )
Consequence
FLG
NM_002016.2 frameshift
NM_002016.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -1.01
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 exon, not predicted to undergo nonsense mediated mRNA decay. There are 89 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
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Variant 1-152311183-AC-A is Pathogenic according to our data. Variant chr1-152311183-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 50931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLG | NM_002016.2 | c.3702del | p.Ser1235HisfsTer211 | frameshift_variant | 3/3 | ENST00000368799.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLG | ENST00000368799.2 | c.3702del | p.Ser1235HisfsTer211 | frameshift_variant | 3/3 | 1 | NM_002016.2 | P1 | |
FLG-AS1 | ENST00000653548.1 | n.390-21397del | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000146 AC: 22AN: 150212Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.000171 AC: 43AN: 251482Hom.: 0 AF XY: 0.000206 AC XY: 28AN XY: 135914
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GnomAD4 exome AF: 0.000282 AC: 412AN: 1461888Hom.: 0 Cov.: 101 AF XY: 0.000292 AC XY: 212AN XY: 727244
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GnomAD4 genome ? AF: 0.000146 AC: 22AN: 150212Hom.: 0 Cov.: 30 AF XY: 0.000178 AC XY: 13AN XY: 73200
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ichthyosis vulgaris Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Oct 02, 2023 | The FLG c.3702del (p.Ser1235HisfsTer211) variant, also known as 3702delG, has been described in the heterozygous and compound heterozygous state in individuals affected with atopic dermatitis or icthyosis vulgaris and is associated with an increased risk for atopic dermatitis (OR 7.9; Brown SJ et al., PMID: 19681860; Gruber R et al., PMID: 21514438; Mohiuddin MS et al., PMID: 24565632; Sandilands A et al., PMID: 17417636). This variant has been reported in the ClinVar database as a germline pathogenic variant by two submitters. This variant is only observed on 49/282666 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a frameshift by deleting a single nucleotide, leading to a premature termination codon; however, because this occurs in the last exon, this is not predicted to lead to nonsense mediated decay. There are at least three pathogenic variants that introduce a premature termination codon that occur downstream of this variant. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Provincial Medical Genetics Program of British Columbia, University of British Columbia | Jan 01, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 04, 2023 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 16, 2023 | Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 2827 amino acids are lost and replaced with 210 incorrect amino acids Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 31629803, 25390410, 21514438, 24565632, 16810297, 19681860, 17417636, 29266469, 28927888, 31589614) - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at