rs11584340

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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:

FLG-AS1 (HGNC:):

FLG-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 666623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-152313454-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
FLG	NM_002016.2 linkuse as main transcript	c.1432C>T	p.Pro478Ser	missense_variant	3/3	ENST00000368799.2	NP_002007.1	P20930

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLG	ENST00000368799.2 linkuse as main transcript	c.1432C>T	p.Pro478Ser	missense_variant	3/3	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

GnomAD3 exomes

AF:

0.273

AC:

68518

AN:

251380

Hom.:

12341

AF XY:

0.273

AC XY:

37059

AN XY:

135868

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 SAS exome

AF:

0.424

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

Gnomad4 AFR exome

AF:

0.135

Gnomad4 AMR exome

AF:

0.437

Gnomad4 ASJ exome

AF:

0.303

Gnomad4 EAS exome

AF:

0.606

Gnomad4 SAS exome

AF:

0.411

Gnomad4 FIN exome

AF:

0.177

Gnomad4 NFE exome

AF:

0.159

Gnomad4 OTH exome

AF:

0.237

GnomAD4 genome

AF:

0.203

AC:

30790

AN:

151422

Hom.:

4073

Cov.:

AF XY:

0.215

AC XY:

15863

AN XY:

73952

show subpopulations

Gnomad4 AFR

AF:

0.138

Gnomad4 AMR

AF:

0.358

Gnomad4 ASJ

AF:

0.314

Gnomad4 EAS

AF:

0.592

Gnomad4 SAS

AF:

0.434

Gnomad4 FIN

AF:

0.187

Gnomad4 NFE

AF:

0.159

Gnomad4 OTH

AF:

0.230

Alfa

AF:

0.172

Hom.:

1495

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2020	This variant is associated with the following publications: (PMID: 21219289, 25458912, 18193244, 24521637) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 23, 2016

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

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

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

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over