rs114733570

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.Glu32Ter) 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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 2.76

Variant links:

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]

FLG links:

FLG-AS1 (HGNC:27913): (cervical cancer associated DHX9 suppressive transcript)

FLG-AS1 links:

Genome browser will be placed here

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 127 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	UniProt
FLG	NM_002016.2 linkuse as main transcript	c.94G>T	p.Glu32Ter	stop_gained	2/3	ENST00000368799.2
FLG-AS1	NR_103778.1 linkuse as main transcript	n.914+406C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLG	ENST00000368799.2 linkuse as main transcript	c.94G>T	p.Glu32Ter	stop_gained	2/3	1	NM_002016.2	P1
FLG-AS1	ENST00000653548.1 linkuse as main transcript	n.390-17220C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000123

AC:

AN:

251144

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135750

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000247

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000283

AC:

413

AN:

1461108

Hom.:

Cov.:

AF XY:

0.000259

AC XY:

188

AN XY:

726884

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000363

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000204

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000434

Hom.:

Bravo

AF:

0.000185

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ichthyosis vulgaris

Pathogenic:4

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. -
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]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	May 15, 2023	PVS1, PM2 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

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, criteria provided, single submitter	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	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.60

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.83

MutationTaster

Benign

1.0

Vest4

0.54

GERP RS

5.2

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over