Variant chr1-152307085-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting

The NM_002016.2(FLG):c.7801G>A(p.Asp2601Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,610,448 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 24)

Exomes 𝑓: 0.0017 ( 4 hom. )

Consequence

FLG
NM_002016.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.338

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008227736).

BP6

Variant 1-152307085-C-T is Benign according to our data. Variant chr1-152307085-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445660.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAdExome4 at 4 SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLG	NM_002016.2 linkuse as main transcript	c.7801G>A	p.Asp2601Asn	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.7801G>A	p.Asp2601Asn	missense_variant	3/3	1	NM_002016.2	P1
FLG-AS1	ENST00000653548.1 linkuse as main transcript	n.390-25498C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00112

AC:

166

AN:

148470

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000255

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000603

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000967

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00211

Gnomad OTH

AF:

0.00147

GnomAD3 exomes

AF:

0.000993

AC:

249

AN:

250844

Hom.:

AF XY:

0.00103

AC XY:

140

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.000316

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.00188

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.00169

AC:

2477

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

1190

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000412

Gnomad4 NFE exome

AF:

0.00209

Gnomad4 OTH exome

AF:

0.00147

GnomAD4 genome

AF:

0.00112

AC:

166

AN:

148586

Hom.:

Cov.:

AF XY:

0.000856

AC XY:

AN XY:

72442

show subpopulations

Gnomad4 AFR

AF:

0.000254

Gnomad4 AMR

AF:

0.000602

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000967

Gnomad4 NFE

AF:

0.00211

Gnomad4 OTH

AF:

0.00145

Alfa

AF:

0.00149

Hom.:

Bravo

AF:

0.00124

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00101

AC:

123

EpiCase

AF:

0.00196

EpiControl

AF:

0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ichthyosis vulgaris;C1853965:Dermatitis, atopic, 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jun 30, 2016

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Mar 06, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.0

DANN

Benign

0.73

DEOGEN2

Benign

0.019

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.58

M_CAP

Benign

0.0022

MetaRNN

Benign

0.0082

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

1.0

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.54

REVEL

Benign

0.086

Sift

Benign

0.047

Polyphen

0.61

Vest4

0.042

MVP

0.12

ClinPred

0.012

GERP RS

-2.3

Varity_R

0.035

gMVP

0.034

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