Variant 1-152303083-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002016.2(FLG):c.11803T>C(p.Ser3935Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0183 in 1,614,054 control chromosomes in the GnomAD database, including 4,622 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 0.098 ( 2492 hom., cov: 31)

Exomes 𝑓: 0.010 ( 2130 hom. )

Consequence

FLG
NM_002016.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.990

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=0.0034312606).

BP6

Variant 1-152303083-A-G is Benign according to our data. Variant chr1-152303083-A-G is described in ClinVar as [Benign]. Clinvar id is 1258538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.338 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.11803T>C	p.Ser3935Pro	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.11803T>C	p.Ser3935Pro	missense_variant	3/3	1	NM_002016.2	ENSP00000357789.1		P20930

Frequencies

GnomAD3 genomes

AF:

0.0980

AC:

14899

AN:

152052

Hom.:

2488

Cov.:

show subpopulations

Gnomad AFR

AF:

0.342

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0338

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00208

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00107

Gnomad OTH

AF:

0.0641

GnomAD3 exomes

AF:

0.0255

AC:

6424

AN:

251476

Hom.:

1012

AF XY:

0.0189

AC XY:

2571

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.352

Gnomad AMR exome

AF:

0.0144

Gnomad ASJ exome

AF:

0.00218

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000719

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000853

Gnomad OTH exome

AF:

0.0109

GnomAD4 exome

AF:

0.00998

AC:

14594

AN:

1461884

Hom.:

2130

Cov.:

AF XY:

0.00847

AC XY:

6158

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.349

Gnomad4 AMR exome

AF:

0.0165

Gnomad4 ASJ exome

AF:

0.00153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000904

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000679

Gnomad4 OTH exome

AF:

0.0205

GnomAD4 genome

AF:

0.0981

AC:

14933

AN:

152170

Hom.:

2492

Cov.:

AF XY:

0.0947

AC XY:

7047

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.342

Gnomad4 AMR

AF:

0.0336

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00107

Gnomad4 OTH

AF:

0.0634

Alfa

AF:

0.0181

Hom.:

867

Bravo

AF:

0.109

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.328

AC:

1446

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.0318

AC:

3858

Asia WGS

AF:

0.0210

AC:

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.00148

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.51

DEOGEN2

Benign

0.023

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.0040

LIST_S2

Benign

0.29

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.9

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.71

REVEL

Benign

0.13

Sift

Uncertain

0.0050

Polyphen

0.96

Vest4

0.079

ClinPred

0.022

GERP RS

-0.93

Varity_R

0.12

gMVP

0.0064

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