1-152307547-G-A

Position:

• chr1-152307547-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_002016.2(FLG):​c.7339C>T​(p.Arg2447*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,613,514 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 29)
  • Exomes 𝑓: 0.0040 (14 hom.)
• Consequence: FLG NM_002016.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26 O:1
• Conservation: PhyloP100: -4.90

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-AS1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 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 54 pathogenic variants in the truncated region.
• PP5: Variant 1-152307547-G-A is Pathogenic according to our data. Variant chr1-152307547-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 50932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-152307547-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLG	NM_002016.2	c.7339C>T	p.Arg2447*	stop_gained	3/3	ENST00000368799.2	NP_002007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLG	ENST00000368799.2	c.7339C>T	p.Arg2447*	stop_gained	3/3	1	NM_002016.2	ENSP00000357789.1

Frequencies

GnomAD3 genomes AF: 0.00302 AC: 458 AN: 151616 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000722

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00250

Gnomad FIN AF: 0.00766

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00447

Gnomad OTH AF: 0.00241

GnomAD3 exomes AF: 0.00282 AC: 710 AN: 251408 Hom.: 1 AF XY: 0.00284 AC XY: 386 AN XY: 135878

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00199

Gnomad FIN exome AF: 0.00624

Gnomad NFE exome AF: 0.00421

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00398 AC: 5818 AN: 1461778 Hom.: 14 Cov.: 93 AF XY: 0.00392 AC XY: 2851 AN XY: 727188

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00195

Gnomad4 FIN exome AF: 0.00723

Gnomad4 NFE exome AF: 0.00452

Gnomad4 OTH exome AF: 0.00313

GnomAD4 genome AF: 0.00302 AC: 458 AN: 151736 Hom.: 1 Cov.: 29 AF XY: 0.00279 AC XY: 207 AN XY: 74136

Gnomad4 AFR AF: 0.00104

Gnomad4 AMR AF: 0.000721

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00251

Gnomad4 FIN AF: 0.00766

Gnomad4 NFE AF: 0.00447

Gnomad4 OTH AF: 0.00238

Alfa AF: 0.00302 Hom.: 0

Bravo AF: 0.00249

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00454 AC: 39

ExAC AF: 0.00305 AC: 370

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00409

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:26 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ichthyosis vulgaris Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Jun 08, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_002016.1:c.7339C>T in the FLG gene has an allele frequency of 0.006 in European(non-Finnish) subpopulation in the gnomAD database.This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It has been reported multiple times in association with ichthyosis vulgaris and atopic dermatitis as one of the most prevalent FLG pathogenic variants among Northern Europeans (PMID: 17417636; 19874431; 27363669). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PVS1; PM2; PS4. -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Nov 10, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Nov 07, 2023	The FLG c.7339C>T (p.Arg2447Ter) variant has been reported in several individuals affected with ichthyosis vulgaris and atopic dermatitis and is reported in a compound heterozygous state with a pathogenic or likely pathogenic variant in at least at least one individual, and in a heterozygous state in over 100 individuals (González-Tarancón R et al., PMID: 31637781; Greisenegger E et al., PMID: 19874431; Gruber R et al., PMID: 19785597; Sandilands A et al., PMID: 17417636; Schuttelaar M et al., PMID: 19839980; Timmerman JG et al., PMID: 26451970; Weidinger S et al., PMID: 18396323). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.65% in the European (non-Finnish) population. This variant has been reported in the ClinVar database as a pathogenic variant by 18 submitters and likely pathogenic by one submitter. 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	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Aug 19, 2022	ACMG classification criteria: PVS1 very strong, PS4 strong, BS1 strong -
Pathogenic, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	Oct 24, 2023	This sequence variant is a single base substitution (C>T) at coding nucleotide 7339 that replaces an arginine codon with a premature termition sigl in exon 3 of 3 of the FLG gene. This variant is expected to truncate the FLG encoded profilaggrin protein, thereby disrupting the filaggrin 7 repeat and elimiting the remaining filaggrin repeats and C termil domain (PMID: 17502856). Loss of the C termil domain prevents processing profilaggrin into filaggrin monomers, generating a loss of function variant (PMID: 17417636, 22071473). This previously reported (ClinVar 50932), well-documented variant is associated with dermatitis and ichthyosis vulgaris (PMID: 17417636, 19874431, 27363669, 31637781, 32066784, 31365035, 33715246). This variant is present in 814/282684 alleles (0.3%), including 1 homozygote, in the gnomAD control population dataset. Protein studies on p.R501Ter/p.R2447Ter compound heterozygous cell lysates showed that profilaggrin was greatly reduced and filaggrin was absent (PMID: 17417636). Given this information, we consider this a pathogenic variant. ACMG Criteria: PS3, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 13, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	May 18, 2021	- -

not provided Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	FLG: PM3:Very Strong, PVS1:Strong, PM2:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Mar 07, 2023	PVS1, PS3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital	Feb 02, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2020	Recurrent variant that has been reported multiple times in association with ichthyosis vulgaris and atopic dermatitis as one of the more prevalent FLG pathogenic variants among Northern Europeans (Sandilands et al., 2007; Greisenegger et al., 2010; Gimalova et al., 2016); Nonsense variant in the C-terminus predicted to result in protein truncation; other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 26451970, 17417636, 31365035, 19874431, 19839980, 22951058, 19785597, 22995991, 21377035, 28213896, 27363669, 29068602, 29428354, 29054605, 30665703, 31589614, 33144682) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Dermatitis, atopic, 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 06, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Aug 20, 2021	PVS1, PS2, BS2 -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -

Ichthyosis vulgaris;C1853965:Dermatitis, atopic, 2 Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant classified as Pathogenic and reported on 09-09-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PVS1_Strong+PS4+PP4 -

FLG-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 02, 2021

The FLG c.7339C>T (p.Arg2447Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of the available literature, the p.Arg2447Ter variant has been identified in a heterozygous state in at least 32 individuals with atopic dermatitis (Weidinger et al. 2008; Greisenegger et al. 2009; Gimalova et al. 2016; González-Tarancon et al. 2020). The p.Arg2447Ter variant was also reported in a heterozygous state in 28 matched population control subjects, and is reported at a frequency of 0.006488 in the European (Finnish) population of the Genome Aggregation Database (version 2.1.1). This allele frequency is high but is consistent with high prevalence and variable severity seen in affected individuals. Based on the evidence, the p.Arg2447Ter variant is classified as pathogenic for FLG-related disorders. -

Dermatitis, atopic Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The observed stop gained variant c.7339C>T(p.Arg2447Ter) in FLG gene has been reported in heterozygous state in multiple individuals with Ichthyosis vulgaris and atopic dermatitis. This recurrent variant is one of the more prevalent FLG pathogenic variants among Northern Europeans (González-Tarancón R, et al., 2020, Gimalova et al., 2016). The c.7339C>T variant has 0.2% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing (González-Tarancón R, et al., 2020). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	35
DANN	Benign	0.97
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.0047	N
Vest4		0.36
GERP RS		-2.9

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

Other links and lift over

dbSNP: rs138726443; hg19: chr1-152280023;