rs146466242

chr1-152302822-T-Achr1-152302822-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Moderate PP5

The NM_002016.2(FLG):c.12064A>T(p.Lys4022Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000452 in 1,614,234 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00043 (2 hom.)
• Consequence: FLG NM_002016.2 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: -1.06

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 Uncertain_significance. Variant got 3 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. Fraction of 0.01 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PP5: Variant 1-152302822-T-A is Pathogenic according to our data. Variant chr1-152302822-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126848.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}. Variant chr1-152302822-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLG	NM_002016.2	c.12064A>T	p.Lys4022Ter	stop_gained	3/3	ENST00000368799.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLG	ENST00000368799.2	c.12064A>T	p.Lys4022Ter	stop_gained	3/3	1	NM_002016.2	P1
FLG-AS1	ENST00000653548.1	n.390-29761T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152232 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0173

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00143 AC: 359 AN: 251322 Hom.: 1 AF XY: 0.00132 AC XY: 179 AN XY: 135822

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0195

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000434 AC: 634 AN: 1461884 Hom.: 2 Cov.: 31 AF XY: 0.000408 AC XY: 297 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0154

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152350 Hom.: 0 Cov.: 31 AF XY: 0.000658 AC XY: 49 AN XY: 74502

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0173

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000677 Hom.: 0

Bravo AF: 0.00112

ExAC AF: 0.00138 AC: 167

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ichthyosis vulgaris Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	literature only	OMIM	Jul 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2022	Immunohistochemical staining for filaggrin in the epidermis of patients with atopic eczema harboring this variant revealed residual, but markedly reduced, filaggrin expression compared to controls (Nemoto-Hasebe et al., 2009); Nonsense variant, located in the C-terminal incomplete filaggrin repeat, predicted to result in protein truncation, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 27339295, 27519469, 22407025, 29380403, 30810250, 30530433, 19663875, 28143684, 28842327, 25997159, 29122406, 27366014, 28120571, 34426522, 33047146) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	34
Dann	Benign	0.91
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.018	N
MutationTaster	Benign	1.0	D
Vest4		0.47
GERP RS		-3.8

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: rs146466242; hg19: chr1-152275298;