rs397507563

Positions:

• chr1-152311183-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002016.2(FLG):​c.3702delG​(p.Ser1235fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000269 in 1,612,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: FLG NM_002016.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -1.01

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 18 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 104 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-152311183-AC-A is Pathogenic according to our data. Variant chr1-152311183-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 50931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLG	NM_002016.2	c.3702delG	p.Ser1235fs	frameshift_variant	3/3	ENST00000368799.2	NP_002007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLG	ENST00000368799.2	c.3702delG	p.Ser1235fs	frameshift_variant	3/3	1	NM_002016.2	ENSP00000357789.1

Frequencies

GnomAD3 genomes AF: 0.000146 AC: 22 AN: 150212 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000207

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000171 AC: 43 AN: 251482 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135914

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000282 AC: 412 AN: 1461888 Hom.: 0 Cov.: 101 AF XY: 0.000292 AC XY: 212 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000312

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000146 AC: 22 AN: 150212 Hom.: 0 Cov.: 30 AF XY: 0.000178 AC XY: 13 AN XY: 73200

Gnomad4 AFR AF: 0.000147

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000213

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000207

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000132

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ichthyosis vulgaris Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Oct 02, 2023	The FLG c.3702del (p.Ser1235HisfsTer211) variant, also known as 3702delG, has been described in the heterozygous and compound heterozygous state in individuals affected with atopic dermatitis or icthyosis vulgaris and is associated with an increased risk for atopic dermatitis (OR 7.9; Brown SJ et al., PMID: 19681860; Gruber R et al., PMID: 21514438; Mohiuddin MS et al., PMID: 24565632; Sandilands A et al., PMID: 17417636). This variant has been reported in the ClinVar database as a germline pathogenic variant by two submitters. This variant is only observed on 49/282666 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a frameshift by deleting a single nucleotide, leading to a premature termination codon; however, because this occurs in the last exon, this is not predicted to lead to nonsense mediated decay. There are at least three pathogenic variants that introduce a premature termination codon that occur downstream of this variant. 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	Baylor Genetics	Oct 04, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Provincial Medical Genetics Program of British Columbia, University of British Columbia	Jan 01, 2022	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 24, 2024

Frameshift variant predicted to result in abnormal protein length as the last 2827 amino acids are replaced with 210 different amino acids, and other similar variants have been reported in HGMD; This variant is associated with the following publications: (PMID: 31629803, 25390410, 21514438, 24565632, 16810297, 19681860, 17417636, 29266469, 28927888, 31589614, 16444271) -

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: rs397507563; hg19: chr1-152283659;