1-152302796-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.76

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-AS1 (HGNC:27913): (cervical cancer associated DHX9 suppressive transcript)

ACMG classification

Verdict is Benign. Variant got -21 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 GnomAd at 7 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLG	NM_002016.2	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	c.12090G>A	p.Thr4030=	synonymous_variant	3/3	1	NM_002016.2	P1
FLG-AS1	ENST00000653548.1	n.390-29787C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 357 AN: 152150 Hom.: 7 Cov.: 31

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.: 16 AF XY: 0.00293 AC XY: 398 AN XY: 135828

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.: 45 Cov.: 31 AF XY: 0.00149 AC XY: 1080 AN XY: 727238

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.: 7 Cov.: 31 AF XY: 0.00244 AC XY: 182 AN XY: 74450

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.: 0

Bravo AF: 0.00284

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FLG-related disorder Benign:1

Benign, criteria provided, single submitter

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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

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

Other links and lift over

dbSNP: rs117440780; hg19: chr1-152275272; COSMIC: COSV64238804;