1-152309169-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 8P and 5B. PVS1 BS1_Supporting BS2

The NM_002016.2(FLG):c.5717C>A(p.Ser1906Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,613,260 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1906S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0063 (10 hom., cov: 30)
  • Exomes 𝑓: 0.00087 (11 hom.)
• Consequence: FLG NM_002016.2 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 B:1
• Conservation: PhyloP100: -0.370

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. There are 66 pathogenic variants in the truncated region.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00625 (950/151908) while in subpopulation AFR AF= 0.0199 (824/41472). AF 95% confidence interval is 0.0187. There are 10 homozygotes in gnomad4. There are 446 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 10 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLG	NM_002016.2	c.5717C>A	p.Ser1906Ter	stop_gained	3/3	ENST00000368799.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLG	ENST00000368799.2	c.5717C>A	p.Ser1906Ter	stop_gained	3/3	1	NM_002016.2	P1
FLG-AS1	ENST00000653548.1	n.390-23414G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00625 AC: 949 AN: 151790 Hom.: 10 Cov.: 30

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00256

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0127

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00529

GnomAD3 exomes AF: 0.00163 AC: 410 AN: 250964 Hom.: 4 AF XY: 0.00150 AC XY: 203 AN XY: 135676

Gnomad AFR exome AF: 0.00811

Gnomad AMR exome AF: 0.000637

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0133

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000870 AC: 1272 AN: 1461352 Hom.: 11 Cov.: 106 AF XY: 0.000843 AC XY: 613 AN XY: 726992

Gnomad4 AFR exome AF: 0.0190

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00932

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000486

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00625 AC: 950 AN: 151908 Hom.: 10 Cov.: 30 AF XY: 0.00601 AC XY: 446 AN XY: 74234

Gnomad4 AFR AF: 0.0199

Gnomad4 AMR AF: 0.00256

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0127

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00524

Alfa AF: 0.000297 Hom.: 0

ExAC AF: 0.00278 AC: 337

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ichthyosis vulgaris Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_002016.1:c.5717C>A in the FLG gene has an allele frequency of 0.013 in East Asia 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. The c.5717C>A (p.Ser1906*) variant has been detected in a patient affected with ichthyosis vulgaris (PMID: 28407221). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PVS1; PM2_supporting; PP4. -
Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

research

H3Africa Consortium

Oct 28, 2020

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.051, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	35
Dann	Benign	0.91
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.010	N
MutationTaster	Benign	1.0	D
Vest4		0.26
GERP RS		-1.6

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: rs141784184; hg19: chr1-152281645;