Genetic Variant FLG:p.Arg1699Cys (chr1-152309791-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_002016.2(FLG):c.5095C>T(p.Arg1699Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,613,668 control chromosomes in the GnomAD database, including 33,339 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1699H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.16 ( 3131 hom., cov: 30)

Exomes 𝑓: 0.17 ( 30208 hom. )

Consequence

FLG
NM_002016.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0710

Publications

29 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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.5109176E-5).

BP6

Variant 1-152309791-G-A is Benign according to our data. Variant chr1-152309791-G-A is described in ClinVar as [Benign]. Clinvar id is 2585649.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.552 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLG	NM_002016.2 link	c.5095C>T	p.Arg1699Cys	missense_variant	Exon 3 of 3	ENST00000368799.2	NP_002007.1	P20930

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLG	ENST00000368799.2 link	c.5095C>T	p.Arg1699Cys	missense_variant	Exon 3 of 3	1	NM_002016.2	ENSP00000357789.1		P20930

Frequencies

GnomAD3 genomes

AF:

0.157

AC:

23815

AN:

151676

Hom.:

3128

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0341

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.326

Gnomad ASJ

AF:

0.293

Gnomad EAS

AF:

0.570

Gnomad SAS

AF:

0.377

Gnomad FIN

AF:

0.180

Gnomad MID

AF:

0.215

Gnomad NFE

AF:

0.135

Gnomad OTH

AF:

0.196

GnomAD2 exomes

AF:

0.242

AC:

60910

AN:

251468

AF XY:

0.242

show subpopulations

Gnomad AFR exome

AF:

0.0290

Gnomad AMR exome

AF:

0.428

Gnomad ASJ exome

AF:

0.280

Gnomad EAS exome

AF:

0.560

Gnomad FIN exome

AF:

0.171

Gnomad NFE exome

AF:

0.142

Gnomad OTH exome

AF:

0.227

GnomAD4 exome

AF:

0.173

AC:

252819

AN:

1461874

Hom.:

30208

Cov.:

AF XY:

0.178

AC XY:

129266

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0265

AC:

888

AN:

33480

American (AMR)

AF:

0.417

AC:

18662

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.279

AC:

7297

AN:

26136

East Asian (EAS)

AF:

0.561

AC:

22282

AN:

39698

South Asian (SAS)

AF:

0.356

AC:

30708

AN:

86256

European-Finnish (FIN)

AF:

0.167

AC:

8942

AN:

53420

Middle Eastern (MID)

AF:

0.247

AC:

1422

AN:

5768

European-Non Finnish (NFE)

AF:

0.135

AC:

150177

AN:

1111996

Other (OTH)

AF:

0.206

AC:

12441

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

14075

28150

42224

56299

70374

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5816

11632

17448

23264

29080

<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:

0.157

AC:

23815

AN:

151794

Hom.:

3131

Cov.:

AF XY:

0.168

AC XY:

12488

AN XY:

74166

show subpopulations

African (AFR)

AF:

0.0341

AC:

1411

AN:

41428

American (AMR)

AF:

0.327

AC:

4991

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.293

AC:

1014

AN:

3466

East Asian (EAS)

AF:

0.570

AC:

2890

AN:

5074

South Asian (SAS)

AF:

0.375

AC:

1796

AN:

4784

European-Finnish (FIN)

AF:

0.180

AC:

1896

AN:

10550

Middle Eastern (MID)

AF:

0.224

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.136

AC:

9204

AN:

67926

Other (OTH)

AF:

0.193

AC:

406

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

916

1832

2749

3665

4581

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

258

516

774

1032

1290

<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:

0.152

Hom.:

7402

Bravo

AF:

0.166

TwinsUK

AF:

0.136

AC:

504

ALSPAC

AF:

0.137

AC:

527

ESP6500AA

AF:

0.0365

AC:

161

ESP6500EA

AF:

0.144

AC:

1240

ExAC

AF:

0.229

AC:

27771

Asia WGS

AF:

0.455

AC:

1581

AN:

3478

EpiCase

AF:

0.151

EpiControl

AF:

0.147

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Ichthyosis vulgaris

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.032

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.63

MetaRNN

Benign

0.000055

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

-0.071

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.3

REVEL

Benign

0.054

Sift

Uncertain

0.0020

Polyphen

1.0

Vest4

0.050

ClinPred

0.038

GERP RS

1.8

Varity_R

0.15

gMVP

0.018

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over