rs200519781

chr1-152311564-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1 PP5_Very_Strong BS2

The NM_002016.2(FLG):c.3321del(p.Gly1109GlufsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,614,004 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00022 (3 hom.)
• Consequence: FLG NM_002016.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: -0.436

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:27913): (cervical cancer associated DHX9 suppressive transcript)

ACMG classification

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 92 pathogenic variants in the truncated region.
• PP5: Variant 1-152311564-CT-C is Pathogenic according to our data. Variant chr1-152311564-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 420115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-152311564-CT-C is described in Lovd as [Pathogenic]. Variant chr1-152311564-CT-C is described in Lovd as [Likely_pathogenic].
• BS2: High Homozygotes in GnomAdExome at 6 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLG	NM_002016.2	c.3321del	p.Gly1109GlufsTer13	frameshift_variant	3/3	ENST00000368799.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLG	ENST00000368799.2	c.3321del	p.Gly1109GlufsTer13	frameshift_variant	3/3	1	NM_002016.2	P1
FLG-AS1	ENST00000653548.1	n.390-21018del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152010 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0101

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000728 AC: 183 AN: 251488 Hom.: 6 AF XY: 0.000640 AC XY: 87 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00973

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000220 AC: 321 AN: 1461876 Hom.: 3 Cov.: 112 AF XY: 0.000216 AC XY: 157 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00751

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152128 Hom.: 0 Cov.: 31 AF XY: 0.000350 AC XY: 26 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00998

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000684

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ichthyosis vulgaris Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2007	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_002016.1:c.3321delA in the FLG gene has an allele frequency of 0.01 in East Asia subpopulation in the gnomAD database.This variant is predicted to cause loss of normal protein function through protein truncation. The patient's phenotype is highly specific for FLG (PMID: 17291859). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PVS1; PM2_supporting; PP4. -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2022	One of the most common pathogenic variants in the FLG gene reported in individuals of Asian descent with atopic dermatitis and has been described in Chinese, Japanese, Korean, and Singaporean populations (Nomura et al., 2007; Meng et al., 2014); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 2953 amino acids are lost and replaced with 12 incorrect amino acids; This variant is associated with the following publications: (PMID: 21923666, 22407025, 22220561, 23152869, 24858702, 23744309, 17291859, 27519469, 27270549, 18521703, 28120571, 29380403, 30021537, 34426522) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Dermatitis, atopic, 2, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Feb 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

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: rs200519781; hg19: chr1-152284040;