chr1-152303313-C-T

Variant names:

Variant summary

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

The NM_002016.2(FLG):c.11573G>A(p.Arg3858His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00255 in 1,613,978 control chromosomes in the GnomAD database, including 56 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 27 hom., cov: 31)

Exomes 𝑓: 0.0016 ( 29 hom. )

Consequence

FLG
NM_002016.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.36

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:

CCDST (HGNC:55988): (cervical cancer associated DHX9 suppressive transcript)

CCDST 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=0.0028125346).

BP6

Variant 1-152303313-C-T is Benign according to our data. Variant chr1-152303313-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 190986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-152303313-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0115 (1750/152096) while in subpopulation AFR AF= 0.0392 (1625/41478). AF 95% confidence interval is 0.0376. There are 27 homozygotes in gnomad4. There are 823 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 27 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLG	NM_002016.2 link	c.11573G>A	p.Arg3858His	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.11573G>A	p.Arg3858His	missense_variant	Exon 3 of 3	1	NM_002016.2	ENSP00000357789.1		P20930

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1744

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0391

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00465

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.00765

GnomAD3 exomes

AF:

0.00337

AC:

848

AN:

251464

Hom.:

AF XY:

0.00260

AC XY:

354

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.0414

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000457

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000633

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00162

AC:

2370

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

1060

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0404

Gnomad4 AMR exome

AF:

0.00228

Gnomad4 ASJ exome

AF:

0.00115

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000417

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000555

Gnomad4 OTH exome

AF:

0.00330

GnomAD4 genome

AF:

0.0115

AC:

1750

AN:

152096

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

823

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0392

Gnomad4 AMR

AF:

0.00465

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.00757

Alfa

AF:

0.000689

Hom.:

Bravo

AF:

0.0131

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0404

AC:

178

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00413

AC:

502

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Sep 28, 2016

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.0040

DANN

Benign

0.50

DEOGEN2

Benign

0.0091

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.00025

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.92

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.38

REVEL

Benign

0.019

Sift

Benign

0.13

Polyphen

0.021

Vest4

0.069

MVP

0.081

ClinPred

0.0015

GERP RS

-6.0

Varity_R

0.019

gMVP

0.013

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