rs140749305

Positions:

• chr1-152306400-C-A
• chr1-152306400-C-G
• chr1-152306400-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002016.2(FLG):​c.8486G>T​(p.Arg2829Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2829H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FLG NM_002016.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.703

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08192527).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLG	NM_002016.2	c.8486G>T	p.Arg2829Leu	missense_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.8486G>T	p.Arg2829Leu	missense_variant	3/3	1	NM_002016.2	ENSP00000357789.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250680 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135654

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.85e-7 AC: 1 AN: 1460342 Hom.: 0 Cov.: 39 AF XY: 0.00000138 AC XY: 1 AN XY: 726572

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.19
DANN	Benign	0.77
DEOGEN2	Benign	0.042	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0084	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.024
Sift	Benign	0.030	D
Polyphen		0.40	B
Vest4		0.15
MutPred		0.41		Loss of MoRF binding (P = 0.0509);
MVP		0.076
ClinPred		0.069	T
GERP RS		-5.7
Varity_R		0.044
gMVP		0.079

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: rs140749305; hg19: chr1-152278876;