Variant chr1-152302796-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_StrongBP6_Very_StrongBP7BS1BS2_Supporting

The NM_002016.2(FLG):c.12090G>A(p.Thr4030=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,614,142 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 7 hom., cov: 31)

Exomes 𝑓: 0.0015 ( 45 hom. )

Consequence

FLG
NM_002016.2 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.76

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 1-152302796-C-T is Benign according to our data. Variant chr1-152302796-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1211343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.76 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00237 (361/152268) while in subpopulation EAS AF= 0.0268 (139/5186). AF 95% confidence interval is 0.0232. There are 7 homozygotes in gnomad4. There are 182 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 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.12090G>A	p.Thr4030=	synonymous_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.12090G>A	p.Thr4030=	synonymous_variant	3/3	1	NM_002016.2	P1
FLG-AS1	ENST00000653548.1 linkuse as main transcript	n.390-29787C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00235

AC:

357

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00333

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00354

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.0267

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00329

AC:

828

AN:

251330

Hom.:

AF XY:

0.00293

AC XY:

398

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.00271

Gnomad AMR exome

AF:

0.00437

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.0298

Gnomad SAS exome

AF:

0.000621

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000238

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00155

AC:

2262

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

1080

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00323

Gnomad4 AMR exome

AF:

0.00398

Gnomad4 ASJ exome

AF:

0.00241

Gnomad4 EAS exome

AF:

0.0402

Gnomad4 SAS exome

AF:

0.000568

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.000157

Gnomad4 OTH exome

AF:

0.00132

GnomAD4 genome

AF:

0.00237

AC:

361

AN:

152268

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

182

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00335

Gnomad4 AMR

AF:

0.00373

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.0268

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000829

Hom.:

Bravo

AF:

0.00284

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

FLG-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 14, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.34

DANN

Benign

0.64

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