rs151103850

Positions:

chr1-152310208-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002016.2(FLG):c.4678C>T(p.Arg1560Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0394 in 1,613,778 control chromosomes in the GnomAD database, including 1,536 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 104 hom., cov: 30)

Exomes 𝑓: 0.040 ( 1432 hom. )

Consequence

FLG
NM_002016.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.56

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=0.0029270947).

BP6

Variant 1-152310208-G-A is Benign according to our data. Variant chr1-152310208-G-A is described in ClinVar as [Benign]. Clinvar id is 402868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-152310208-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0297 (4509/151892) while in subpopulation NFE AF= 0.0435 (2954/67960). AF 95% confidence interval is 0.0422. There are 104 homozygotes in gnomad4. There are 2189 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 104 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLG	NM_002016.2 linkuse as main transcript	c.4678C>T	p.Arg1560Cys	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.4678C>T	p.Arg1560Cys	missense_variant	3/3	1	NM_002016.2	ENSP00000357789.1		P20930

Frequencies

GnomAD3 genomes

AF:

0.0297

AC:

4509

AN:

151774

Hom.:

104

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00791

Gnomad AMI

AF:

0.0198

Gnomad AMR

AF:

0.0242

Gnomad ASJ

AF:

0.0622

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.0119

Gnomad FIN

AF:

0.0486

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0435

Gnomad OTH

AF:

0.0245

GnomAD3 exomes

AF:

0.0310

AC:

7792

AN:

251470

Hom.:

171

AF XY:

0.0312

AC XY:

4247

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00621

Gnomad AMR exome

AF:

0.0156

Gnomad ASJ exome

AF:

0.0591

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0117

Gnomad FIN exome

AF:

0.0524

Gnomad NFE exome

AF:

0.0427

Gnomad OTH exome

AF:

0.0332

GnomAD4 exome

AF:

0.0404

AC:

59123

AN:

1461886

Hom.:

1432

Cov.:

AF XY:

0.0398

AC XY:

28937

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00591

Gnomad4 AMR exome

AF:

0.0164

Gnomad4 ASJ exome

AF:

0.0600

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0137

Gnomad4 FIN exome

AF:

0.0539

Gnomad4 NFE exome

AF:

0.0452

Gnomad4 OTH exome

AF:

0.0370

GnomAD4 genome

AF:

0.0297

AC:

4509

AN:

151892

Hom.:

104

Cov.:

AF XY:

0.0295

AC XY:

2189

AN XY:

74220

show subpopulations

Gnomad4 AFR

AF:

0.00789

Gnomad4 AMR

AF:

0.0241

Gnomad4 ASJ

AF:

0.0622

Gnomad4 EAS

AF:

0.000196

Gnomad4 SAS

AF:

0.0121

Gnomad4 FIN

AF:

0.0486

Gnomad4 NFE

AF:

0.0435

Gnomad4 OTH

AF:

0.0242

Alfa

AF:

0.0398

Hom.:

Bravo

AF:

0.0268

TwinsUK

AF:

0.0496

AC:

184

ALSPAC

AF:

0.0475

AC:

183

ESP6500AA

AF:

0.00704

AC:

ESP6500EA

AF:

0.0410

AC:

353

ExAC

AF:

0.0307

AC:

3722

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0414

EpiControl

AF:

0.0398

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	Jul 05, 2018	This variant is associated with the following publications: (PMID: 31482965) -
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

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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

0.17

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.83

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.049

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.64

MetaRNN

Benign

0.0029

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.3

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.1

REVEL

Benign

0.084

Sift

Benign

0.068

Polyphen

0.98

Vest4

0.031

ClinPred

0.024

GERP RS

0.34

Varity_R

0.057

gMVP

0.020

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