rs11584340

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002016.2(FLG):c.1432C>T(p.Pro478Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,613,236 control chromosomes in the GnomAD database, including 42,398 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 (★★).

Frequency

Genomes: 𝑓 0.20 ( 4073 hom., cov: 29)

Exomes 𝑓: 0.20 ( 38325 hom. )

Consequence

FLG
NM_002016.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.81

Publications

56 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.0032969E-5).

BP6

Variant 1-152313454-G-A is Benign according to our data. Variant chr1-152313454-G-A is described in ClinVar as Benign. ClinVar VariationId is 666623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLG	NM_002016.2 link	c.1432C>T	p.Pro478Ser	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.1432C>T	p.Pro478Ser	missense_variant	Exon 3 of 3	1	NM_002016.2	ENSP00000357789.1		P20930

Frequencies

GnomAD3 genomes

AF:

0.203

AC:

30769

AN:

151304

Hom.:

4065

Cov.:

show subpopulations

Gnomad AFR

AF:

0.138

Gnomad AMI

AF:

0.196

Gnomad AMR

AF:

0.358

Gnomad ASJ

AF:

0.314

Gnomad EAS

AF:

0.592

Gnomad SAS

AF:

0.435

Gnomad FIN

AF:

0.187

Gnomad MID

AF:

0.264

Gnomad NFE

AF:

0.159

Gnomad OTH

AF:

0.233

GnomAD2 exomes

AF:

0.273

AC:

68518

AN:

251380

AF XY:

0.273

show subpopulations

Gnomad AFR exome

AF:

0.135

Gnomad AMR exome

AF:

0.447

Gnomad ASJ exome

AF:

0.304

Gnomad EAS exome

AF:

0.579

Gnomad FIN exome

AF:

0.179

Gnomad NFE exome

AF:

0.165

Gnomad OTH exome

AF:

0.253

GnomAD4 exome

AF:

0.201

AC:

293476

AN:

1461814

Hom.:

38325

Cov.:

AF XY:

0.206

AC XY:

150050

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.135

AC:

4514

AN:

33418

American (AMR)

AF:

0.437

AC:

19532

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.303

AC:

7911

AN:

26136

East Asian (EAS)

AF:

0.606

AC:

24049

AN:

39700

South Asian (SAS)

AF:

0.411

AC:

35485

AN:

86258

European-Finnish (FIN)

AF:

0.177

AC:

9429

AN:

53420

Middle Eastern (MID)

AF:

0.292

AC:

1685

AN:

5764

European-Non Finnish (NFE)

AF:

0.159

AC:

176584

AN:

1112010

Other (OTH)

AF:

0.237

AC:

14287

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

18714

37428

56141

74855

93569

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6738

13476

20214

26952

33690

<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:

0.203

AC:

30790

AN:

151422

Hom.:

4073

Cov.:

AF XY:

0.215

AC XY:

15863

AN XY:

73952

show subpopulations

African (AFR)

AF:

0.138

AC:

5706

AN:

41248

American (AMR)

AF:

0.358

AC:

5457

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.314

AC:

1088

AN:

3466

East Asian (EAS)

AF:

0.592

AC:

2979

AN:

5036

South Asian (SAS)

AF:

0.434

AC:

2059

AN:

4742

European-Finnish (FIN)

AF:

0.187

AC:

1969

AN:

10524

Middle Eastern (MID)

AF:

0.274

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.159

AC:

10792

AN:

67882

Other (OTH)

AF:

0.230

AC:

482

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1121

2242

3363

4484

5605

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

320

640

960

1280

1600

<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:

0.187

Hom.:

3370

Bravo

AF:

0.215

TwinsUK

AF:

0.158

AC:

586

ALSPAC

AF:

0.163

AC:

629

ESP6500AA

AF:

0.140

AC:

615

ESP6500EA

AF:

0.168

AC:

1444

ExAC

AF:

0.261

AC:

31705

Asia WGS

AF:

0.507

AC:

1761

AN:

3478

EpiCase

AF:

0.175

EpiControl

AF:

0.171

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 19, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21219289, 25458912, 18193244, 24521637) -

not specified

Benign:1

May 23, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Pro478Ser in exon 3 of FLG: This variant is not expected to have clinical sign ificance because it has been identified in 58.20% (5010/8608) of East Asian chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs11584340). -

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

0.041

BayesDel_addAF

Benign

-0.88

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.0060

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.018

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.00021

LIST_S2

Benign

0.33

MetaRNN

Benign

0.000010

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.6

PhyloP100

-1.8

PrimateAI

Benign

0.30

PROVEAN

Benign

1.6

REVEL

Benign

0.042

Sift

Benign

1.0

Polyphen

0.020

Vest4

0.010

ClinPred

0.0078

GERP RS

-3.1

Varity_R

0.023

gMVP

0.048

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