Variant chr1-152302977-G-A 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.11909C>T(p.Ser3970Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00654 in 1,614,126 control chromosomes in the GnomAD database, including 491 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 0.012 ( 86 hom., cov: 31)

Exomes 𝑓: 0.0059 ( 405 hom. )

Consequence

FLG
NM_002016.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.90

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:27913): (cervical cancer associated DHX9 suppressive transcript)

FLG-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020753741).

BP6

Variant 1-152302977-G-A is Benign according to our data. Variant chr1-152302977-G-A is described in ClinVar as [Benign]. Clinvar id is 1231239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-152302977-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0838 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLG	NM_002016.2 linkuse as main transcript	c.11909C>T	p.Ser3970Leu	missense_variant	3/3	ENST00000368799.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLG	ENST00000368799.2 linkuse as main transcript	c.11909C>T	p.Ser3970Leu	missense_variant	3/3	1	NM_002016.2	P1
FLG-AS1	ENST00000653548.1 linkuse as main transcript	n.390-29606G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1871

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00258

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0871

Gnomad ASJ

AF:

0.00779

Gnomad EAS

AF:

0.0627

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.0167

GnomAD3 exomes

AF:

0.0211

AC:

5302

AN:

251374

Hom.:

281

AF XY:

0.0170

AC XY:

2312

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.00252

Gnomad AMR exome

AF:

0.112

Gnomad ASJ exome

AF:

0.00923

Gnomad EAS exome

AF:

0.0602

Gnomad SAS exome

AF:

0.00183

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000334

Gnomad OTH exome

AF:

0.0160

GnomAD4 exome

AF:

0.00594

AC:

8687

AN:

1461878

Hom.:

405

Cov.:

AF XY:

0.00540

AC XY:

3927

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00143

Gnomad4 AMR exome

AF:

0.111

Gnomad4 ASJ exome

AF:

0.00819

Gnomad4 EAS exome

AF:

0.0658

Gnomad4 SAS exome

AF:

0.00174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000218

Gnomad4 OTH exome

AF:

0.00775

GnomAD4 genome

AF:

0.0123

AC:

1875

AN:

152248

Hom.:

Cov.:

AF XY:

0.0145

AC XY:

1082

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00258

Gnomad4 AMR

AF:

0.0877

Gnomad4 ASJ

AF:

0.00779

Gnomad4 EAS

AF:

0.0620

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.0165

Alfa

AF:

0.00587

Hom.:

Bravo

AF:

0.0178

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.0160

AC:

1945

Asia WGS

AF:

0.0360

AC:

124

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000889

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	clinical testing	GeneDx	Jul 14, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.49

DEOGEN2

Benign

0.023

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0021

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.7

MutationTaster

Benign

1.0

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.77

REVEL

Benign

0.068

Sift

Uncertain

0.0020

Polyphen

0.90

Vest4

0.11

ClinPred

0.019

GERP RS

2.2

Varity_R

0.049

gMVP

0.0060

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