rs41370446
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_002016.2(FLG):βc.3254_3257delβ(p.Ser1085CysfsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β ).
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 30)
Exomes π: 0.0000014 ( 0 hom. )
Consequence
FLG
NM_002016.2 frameshift
NM_002016.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.98
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 12 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 94 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-152311628-CACTG-C is Pathogenic according to our data. Variant chr1-152311628-CACTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 50928.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLG | NM_002016.2 | c.3254_3257del | p.Ser1085CysfsTer36 | frameshift_variant | 3/3 | ENST00000368799.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLG | ENST00000368799.2 | c.3254_3257del | p.Ser1085CysfsTer36 | frameshift_variant | 3/3 | 1 | NM_002016.2 | P1 | |
FLG-AS1 | ENST00000653548.1 | n.390-20950_390-20947del | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 30
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461886Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727244
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1AN XY: 74306
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 18, 2022 | Identified in the heterozygous state in 22 children from a cohort of individuals with FLG variants, some of which presented with atopic dermatitis (Looman et al., 2021); Frameshift variant predicted to result in protein truncation, as the last 2977 amino acids are replaced with 35 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16444271, 33715246) - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at