rs11582620

chr1-152313650-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002016.2(FLG):c.1236T>C(p.Arg412=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,613,394 control chromosomes in the GnomAD database, including 12,680 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.091 (912 hom., cov: 31)
  • Exomes 𝑓: 0.12 (11768 hom.)
• Consequence: FLG NM_002016.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.63

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=-0.93).
• BP6: Variant 1-152313650-A-G is Benign according to our data. Variant chr1-152313650-A-G is described in ClinVar as [Benign]. Clinvar id is 1259919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-152313650-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.63 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLG	NM_002016.2	c.1236T>C	p.Arg412=	synonymous_variant	3/3	ENST00000368799.2
FLG-AS1	NR_103778.1	n.192A>G		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLG	ENST00000368799.2	c.1236T>C	p.Arg412=	synonymous_variant	3/3	1	NM_002016.2	P1
FLG-AS1	ENST00000653548.1	n.390-18933A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0914 AC: 13834 AN: 151386 Hom.: 914 Cov.: 31

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.0786

Gnomad ASJ AF: 0.0646

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.0871

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.0805

GnomAD3 exomes AF: 0.116 AC: 29148 AN: 251476 Hom.: 1961 AF XY: 0.122 AC XY: 16594 AN XY: 135906

Gnomad AFR exome AF: 0.0178

Gnomad AMR exome AF: 0.0931

Gnomad ASJ exome AF: 0.0614

Gnomad EAS exome AF: 0.102

Gnomad SAS exome AF: 0.201

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.119

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.122 AC: 178877 AN: 1461886 Hom.: 11768 Cov.: 72 AF XY: 0.125 AC XY: 91264 AN XY: 727246

Gnomad4 AFR exome AF: 0.0160

Gnomad4 AMR exome AF: 0.0893

Gnomad4 ASJ exome AF: 0.0656

Gnomad4 EAS exome AF: 0.118

Gnomad4 SAS exome AF: 0.208

Gnomad4 FIN exome AF: 0.128

Gnomad4 NFE exome AF: 0.122

Gnomad4 OTH exome AF: 0.112

GnomAD4 genome AF: 0.0913 AC: 13830 AN: 151508 Hom.: 912 Cov.: 31 AF XY: 0.0932 AC XY: 6893 AN XY: 73998

Gnomad4 AFR AF: 0.0213

Gnomad4 AMR AF: 0.0787

Gnomad4 ASJ AF: 0.0646

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.124

Gnomad4 OTH AF: 0.0787

Alfa AF: 0.111 Hom.: 1627

Bravo AF: 0.0825

Asia WGS AF: 0.117 AC: 407 AN: 3478

EpiCase AF: 0.122

EpiControl AF: 0.115

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

FLG-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 18, 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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	2.1
Dann	Benign	0.46

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: rs11582620; hg19: chr1-152286126; COSMIC: COSV64236548;