1-152305146-G-T

Variant names:

• chr1-152305146-G-T
• rs150597413
• NM_002016.2:c.9740C>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1 PP5_Very_Strong BS2_Supporting

The NM_002016.2(FLG):​c.9740C>A​(p.Ser3247*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00279 in 1,613,830 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0029 (15 hom.)
• Consequence: FLG NM_002016.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: -0.595
• Publications: 179 publications found

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]

CCDST (HGNC:55988): (cervical cancer associated DHX9 suppressive transcript)

ACMG classification

Our verdict: Pathogenic. The variant received 15 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 39 pathogenic variants in the truncated region.
• PP5: Variant 1-152305146-G-T is Pathogenic according to our data. Variant chr1-152305146-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 50930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 15 SD,XL,AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLG	NM_002016.2	c.9740C>A	p.Ser3247*	stop_gained	Exon 3 of 3	ENST00000368799.2	NP_002007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLG	ENST00000368799.2	c.9740C>A	p.Ser3247*	stop_gained	Exon 3 of 3	1	NM_002016.2	ENSP00000357789.1

Frequencies

GnomAD3 genomes AF: 0.00157 AC: 238 AN: 151886 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000677

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00148 AC: 372 AN: 251454 AF XY: 0.00150

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00286

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00292 AC: 4270 AN: 1461828 Hom.: 15 Cov.: 37 AF XY: 0.00280 AC XY: 2039 AN XY: 727208

African (AFR) AF: 0.000478 AC: 16 AN: 33480

American (AMR) AF: 0.000268 AC: 12 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86232

European-Finnish (FIN) AF: 0.000599 AC: 32 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00357 AC: 3975 AN: 1111984

Other (OTH) AF: 0.00386 AC: 233 AN: 60386

GnomAD4 genome AF: 0.00157 AC: 238 AN: 152002 Hom.: 1 Cov.: 30 AF XY: 0.00139 AC XY: 103 AN XY: 74298

African (AFR) AF: 0.000675 AC: 28 AN: 41494

American (AMR) AF: 0.000590 AC: 9 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00288 AC: 196 AN: 67942

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00127 Hom.: 0

Bravo AF: 0.00172

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00135 AC: 164

EpiCase AF: 0.00365

EpiControl AF: 0.00284

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ichthyosis vulgaris Pathogenic:6

Nov 30, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4, PM3_Strong -

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 24, 2023

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single base substitution (C>A) at coding nucleotide 9740 that replaces a serine 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 9 repeat and elimiting the filaggrin 10 repeat and the 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 50930), well-documented variant is associated with atopic dermatitis, ichthyosis vulgaris, and asthma in both the homozygous and compound heterozygous states (PMID: 17417636, 20109745, 31365035, 30665703, 18396323, 19183181). Case-control studies have documented the significant association with this variant with atopic dermatitis (PMID: 17417636, 20109745). In addition, this variant co-segregates with either atopic dermatitis (PMD: 17417636), or ichthyosis vulgaris (PMID: 19785597) in two small pedigrees. This variant is present in 417 of 282,786 alleles (0.15%) in the gnomAD control population dataset. Studies examining the functiol consequence of this variant have not been published, to our knowledge. However, a histologic examition of a skin sample of a heterozygous individual exhibited a reduction in the stratum granulosum layer and less filaggrin than observed in a sample taken from a wildtype individual (PMID: 19183181). Given this information, we consider this a pathogenic variant. ACMG Criteria: PS4, PVS1 -

Jun 24, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FLG c.9740C>A (p.Ser3247X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.0015 in 251454 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in FLG causing Ichthyosis Vulgaris, allowing no conclusion about variant significance. c.9740C>A has been reported in the literature in multiple heterozygous individuals affected with Atopic Dermatitis (e.g. Sandilands_2007), as well as at least one Ichthyosis Vulgaris case who was compound heterozygous with a pathogenic variant (Sitek_2018). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 17502856, 29444371). ClinVar contains an entry for this variant (Variation ID: 50930). Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:5

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 18, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Predisposes to elevated serum IgE levels and allergic sensitization, atopic dermatitis, and asthma (Sandilands et al., 2007; Greisenegger et al., 2010; Ziyab et al., 2012); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 815 amino acids are lost, and 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: 29068602, 29444371, 25533962, 28317091, 30665703, 21377035, 22403702, 26451970, 28479194, 28219068, 27840886, 28571749, 28502108, 28592289, 29428354, 19874431, 31365035, 31589614, 17417636) -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FLG: PM3:Strong, PVS1:Strong, PM2:Supporting -

See cases Pathogenic:1

Nov 13, 2020

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1, PS4 -

FLG-related disorder Pathogenic:1

Apr 05, 2021

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FLG c.9740C>A (p.Ser3247Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of available literature, the p.Ser3247Ter variant has been identified in at least 45 individuals in a heterozygous state and in at least three individuals in a compound heterozygous state. These individuals presented with atopic dermatitis, contact dermatitis (chronic irritant or allergic), or ichthyosis vulgaris (Sandilands et al. 2007; Oji et al. 2009; Greisenegger et al. 2010; Margolis et al. 2012; Mohiuddin et al. 2013; Visser et al. 2013; Sitek et al. 2018). At least one individual with the variant in a compound heterozygous state was shown to have a more severe presentation compared to when the variant was present in a heterozygous state (Oji et al. 2009). Odds ratio for association with FLG-related skin conditions ranged from 1.66 to 7.05, with statistical significance varying across studies. The case-control studies generally showed a higher frequency of the variant in cases when compared to controls (Sandilands et al. 2007; Greisenegger et al. 2010; Visser et al. 2013; Margolis et al. 2019; Wright et al. 2019). It is suggested that the p.Ser3247Ter variant has reduced penetrance compared to other common pathogenic variants in FLG (Sandilands et al. 2007). In addition, follow-up of children enrolled in the Pediatric Eczema Elective Registry showed that affected individuals had faster recovery of the skin condition after treatment with topical medication compared to those carrying other pathogenic FLG variants (Margolis et al. 2012). The p.Ser3247Ter variant was identified in 25 of 4296 control individuals in a heterozygous state (Sandilands et al. 2007; Weidinger et al. 2008; Oji et al. 2009; Greisenegger et al. 2010; Visser et al. 2013; Rupnik et al. 2015), and is reported at a frequency of 0.002819 in the European (non-Finnish) population of the Genome Aggregation Database (version 2.1.1). This allele frequency is high among presumed unaffected individuals, but is consistent with the disease prevalence and penetrance estimates. Oji et al. (2009) evaluated the structure, histology, and antigen mapping using immunofluorescence of skin samples from an individual with ichthyosis vulgaris with the variant in heterozygous state. Filaggrin antigen was reduced and the stratum granulosum was reduced, but focally normal. Based on the collective evidence, the p.Ser3247Ter variant is classified as likely pathogenic for FLG-related disorders. -

Dermatitis, atopic, 2 Pathogenic:1

Oct 16, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This FLG variant (rs150597413) is present in a large population dataset (gnomAD: 417/282786 total alleles; 0.15%; no homozygotes) and has an entry in ClinVar. It is considered one of the more common disease-associated variants in individuals with European ancestry7. This nonsense variant in FLG is predicted to lead to a premature stop codon (PTC) in the last exon of the gene, likely escaping nonsense-mediated decay and resulting in a truncated protein product. Although the exact function of the C-terminal segment after this PTC is unclear, there are reports of disease-associated nonsense variants located downstream of c.9740C>A. Not everyone with a disease-associated variant will develop this disorder, consistent with an increased frequency of this variant in controls from the European population (0.28%). We consider c.9740C>A to be likely pathogenic. -

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

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Pathogenic and reported on 10-13-2023 by GeneDx. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	36
DANN	Benign	0.97
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.038	N
PhyloP100		-0.59
Vest4		0.34
GERP RS		-0.016
Mutation Taster		=21/179	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs150597413; hg19: chr1-152277622;