rs12756586

Positions:

• chr1-152311948-G-C
• chr1-152311948-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002016.2(FLG):​c.2938C>G​(p.His980Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0255 in 1,577,942 control chromosomes in the GnomAD database, including 708 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (52 hom., cov: 30)
  • Exomes 𝑓: 0.026 (656 hom.)
• Consequence: FLG NM_002016.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.19

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023139417).
• BP6: Variant 1-152311948-G-C is Benign according to our data. Variant chr1-152311948-G-C is described in ClinVar as [Benign]. Clinvar id is 402869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-152311948-G-C is described in Lovd as [Likely_benign]. Variant chr1-152311948-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLG	NM_002016.2	c.2938C>G	p.His980Asp	missense_variant	3/3	ENST00000368799.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLG	ENST00000368799.2	c.2938C>G	p.His980Asp	missense_variant	3/3	1	NM_002016.2	P1
FLG-AS1	ENST00000653548.1	n.390-20635G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3449 AN: 137672 Hom.: 52 Cov.: 30

Gnomad AFR AF: 0.0261

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0231

Gnomad ASJ AF: 0.0224

Gnomad EAS AF: 0.0288

Gnomad SAS AF: 0.0709

Gnomad FIN AF: 0.00891

Gnomad MID AF: 0.0417

Gnomad NFE AF: 0.0240

Gnomad OTH AF: 0.0249

GnomAD3 exomes AF: 0.0236 AC: 5885 AN: 249840 Hom.: 106 AF XY: 0.0255 AC XY: 3454 AN XY: 135198

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.0140

Gnomad ASJ exome AF: 0.0233

Gnomad EAS exome AF: 0.0190

Gnomad SAS exome AF: 0.0565

Gnomad FIN exome AF: 0.00836

Gnomad NFE exome AF: 0.0225

Gnomad OTH exome AF: 0.0233

GnomAD4 exome AF: 0.0255 AC: 36725 AN: 1440190 Hom.: 656 Cov.: 114 AF XY: 0.0266 AC XY: 19040 AN XY: 716578

Gnomad4 AFR exome AF: 0.0277

Gnomad4 AMR exome AF: 0.0142

Gnomad4 ASJ exome AF: 0.0227

Gnomad4 EAS exome AF: 0.0467

Gnomad4 SAS exome AF: 0.0586

Gnomad4 FIN exome AF: 0.00927

Gnomad4 NFE exome AF: 0.0236

Gnomad4 OTH exome AF: 0.0241

GnomAD4 genome AF: 0.0250 AC: 3447 AN: 137752 Hom.: 52 Cov.: 30 AF XY: 0.0255 AC XY: 1709 AN XY: 67010

Gnomad4 AFR AF: 0.0261

Gnomad4 AMR AF: 0.0230

Gnomad4 ASJ AF: 0.0224

Gnomad4 EAS AF: 0.0288

Gnomad4 SAS AF: 0.0713

Gnomad4 FIN AF: 0.00891

Gnomad4 NFE AF: 0.0240

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0126 Hom.: 2

TwinsUK AF: 0.0213 AC: 79

ALSPAC AF: 0.0259 AC: 100

ExAC AF: 0.0255 AC: 3094

EpiCase AF: 0.0234

EpiControl AF: 0.0219

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Gene associated with ichthyosis/dermatitis -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Ichthyosis vulgaris Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.038
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0020
DANN	Benign	0.47
DEOGEN2	Benign	0.026	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.00029	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.2	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.023
Sift	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.022
ClinPred		0.0033	T
GERP RS		-6.6
Varity_R		0.034
gMVP		0.0099

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: rs12756586; hg19: chr1-152284424; COSMIC: COSV64236115; COSMIC: COSV64236115;