rs138726443

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1PP5_Very_StrongBS2_Supporting

The NM_002016.2(FLG):c.7339C>T(p.Arg2447*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,613,514 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0030 ( 1 hom., cov: 29)

Exomes 𝑓: 0.0040 ( 14 hom. )

Consequence

FLG
NM_002016.2 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:30O:1

Conservation

PhyloP100: -4.90

Publications

215 publications found

Variant links:

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 links:

CCDST (HGNC:55988): (cervical cancer associated DHX9 suppressive transcript)

CCDST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 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 88 pathogenic variants in the truncated region.

PP5

Variant 1-152307547-G-A is Pathogenic according to our data. Variant chr1-152307547-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 50932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 14 SD,XL,AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002016.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLG	NM_002016.2	MANE Select	c.7339C>T	p.Arg2447*	stop_gained	Exon 3 of 3	NP_002007.1	P20930
CCDST	NR_186761.1		n.578-25036G>A		intron	N/A
CCDST	NR_186762.1		n.180-25036G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLG	ENST00000368799.2	TSL:1 MANE Select	c.7339C>T	p.Arg2447*	stop_gained	Exon 3 of 3	ENSP00000357789.1	P20930
CCDST	ENST00000420707.5	TSL:5	n.462+5714G>A		intron	N/A
CCDST	ENST00000593011.5	TSL:4	n.376+5714G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00302

AC:

458

AN:

151616

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.000722

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00250

Gnomad FIN

AF:

0.00766

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00447

Gnomad OTH

AF:

0.00241

GnomAD2 exomes

AF:

0.00282

AC:

710

AN:

251408

AF XY:

0.00284

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00624

Gnomad NFE exome

AF:

0.00421

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00398

AC:

5818

AN:

1461778

Hom.:

Cov.:

AF XY:

0.00392

AC XY:

2851

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33474

American (AMR)

AF:

0.000447

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00195

AC:

168

AN:

86254

European-Finnish (FIN)

AF:

0.00723

AC:

386

AN:

53420

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00452

AC:

5026

AN:

1111954

Other (OTH)

AF:

0.00313

AC:

189

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

496

992

1487

1983

2479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

384

576

768

960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00302

AC:

458

AN:

151736

Hom.:

Cov.:

AF XY:

0.00279

AC XY:

207

AN XY:

74136

show subpopulations

African (AFR)

AF:

0.00104

AC:

AN:

41344

American (AMR)

AF:

0.000721

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5080

South Asian (SAS)

AF:

0.00251

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.00766

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00447

AC:

304

AN:

67938

Other (OTH)

AF:

0.00238

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00259

Hom.:

Bravo

AF:

0.00249

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00454

AC:

ExAC

AF:

0.00305

AC:

370

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00403

EpiControl

AF:

0.00409

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ichthyosis vulgaris (13)

not provided (10)

Dermatitis, atopic, 2 (3)

Ichthyosis vulgaris;C1853965:Dermatitis, atopic, 2 (3)

Dermatitis, atopic (1)

FLG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.021

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Benign

0.97

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.0047

PhyloP100

-4.9

Vest4

0.36

GERP RS

-2.9

Mutation Taster

=5/195

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over