1-152314831-C-G

Position:

• chr1-152314831-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002016.2(FLG):​c.139-84G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0184 in 1,561,218 control chromosomes in the GnomAD database, including 4,518 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.098 (2488 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (2030 hom.)
• Consequence: FLG NM_002016.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.45

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-152314831-C-G is Benign according to our data. Variant chr1-152314831-C-G is described in ClinVar as [Benign]. Clinvar id is 1245429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLG	NM_002016.2	c.139-84G>C		intron_variant		ENST00000368799.2	NP_002007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLG	ENST00000368799.2	c.139-84G>C		intron_variant		1	NM_002016.2	ENSP00000357789.1

Frequencies

GnomAD3 genomes AF: 0.0981 AC: 14886 AN: 151700 Hom.: 2484 Cov.: 32

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0339

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00209

Gnomad FIN AF: 0.0000949

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.0643

GnomAD4 exome AF: 0.00985 AC: 13883 AN: 1409398 Hom.: 2030 Cov.: 25 AF XY: 0.00843 AC XY: 5916 AN XY: 702070

Gnomad4 AFR exome AF: 0.350

Gnomad4 AMR exome AF: 0.0170

Gnomad4 ASJ exome AF: 0.00144

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000941

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000682

Gnomad4 OTH exome AF: 0.0204

GnomAD4 genome AF: 0.0983 AC: 14921 AN: 151820 Hom.: 2488 Cov.: 32 AF XY: 0.0951 AC XY: 7053 AN XY: 74200

Gnomad4 AFR AF: 0.343

Gnomad4 AMR AF: 0.0337

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00188

Gnomad4 FIN AF: 0.0000949

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.0636

Alfa AF: 0.00457 Hom.: 8

Bravo AF: 0.109

Asia WGS AF: 0.0210 AC: 75 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.087
DANN	Benign	0.37

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: rs3126082; hg19: chr1-152287307;