rs12405278

chr1-152309791-G-Achr1-152309791-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002016.2(FLG):c.5095C>T(p.Arg1699Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,613,668 control chromosomes in the GnomAD database, including 33,339 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.16 (3131 hom., cov: 30)
  • Exomes 𝑓: 0.17 (30208 hom.)
• Consequence: FLG NM_002016.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0710

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.5109176E-5).
• BP6: Variant 1-152309791-G-A is Benign according to our data. Variant chr1-152309791-G-A is described in ClinVar as [Benign]. Clinvar id is 2585649.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-152309791-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.552 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLG	NM_002016.2	c.5095C>T	p.Arg1699Cys	missense_variant	3/3	ENST00000368799.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLG	ENST00000368799.2	c.5095C>T	p.Arg1699Cys	missense_variant	3/3	1	NM_002016.2	P1
FLG-AS1	ENST00000653548.1	n.390-22792G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23815 AN: 151676 Hom.: 3128 Cov.: 30

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.570

Gnomad SAS AF: 0.377

Gnomad FIN AF: 0.180

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.196

GnomAD3 exomes AF: 0.242 AC: 60910 AN: 251468 Hom.: 10527 AF XY: 0.242 AC XY: 32911 AN XY: 135904

Gnomad AFR exome AF: 0.0290

Gnomad AMR exome AF: 0.428

Gnomad ASJ exome AF: 0.280

Gnomad EAS exome AF: 0.560

Gnomad SAS exome AF: 0.368

Gnomad FIN exome AF: 0.171

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.227

GnomAD4 exome AF: 0.173 AC: 252819 AN: 1461874 Hom.: 30208 Cov.: 81 AF XY: 0.178 AC XY: 129266 AN XY: 727242

Gnomad4 AFR exome AF: 0.0265

Gnomad4 AMR exome AF: 0.417

Gnomad4 ASJ exome AF: 0.279

Gnomad4 EAS exome AF: 0.561

Gnomad4 SAS exome AF: 0.356

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.206

GnomAD4 genome AF: 0.157 AC: 23815 AN: 151794 Hom.: 3131 Cov.: 30 AF XY: 0.168 AC XY: 12488 AN XY: 74166

Gnomad4 AFR AF: 0.0341

Gnomad4 AMR AF: 0.327

Gnomad4 ASJ AF: 0.293

Gnomad4 EAS AF: 0.570

Gnomad4 SAS AF: 0.375

Gnomad4 FIN AF: 0.180

Gnomad4 NFE AF: 0.136

Gnomad4 OTH AF: 0.193

Alfa AF: 0.150 Hom.: 3929

Bravo AF: 0.166

TwinsUK AF: 0.136 AC: 504

ALSPAC AF: 0.137 AC: 527

ESP6500AA AF: 0.0365 AC: 161

ESP6500EA AF: 0.144 AC: 1240

ExAC AF: 0.229 AC: 27771

Asia WGS AF: 0.455 AC: 1581 AN: 3478

EpiCase AF: 0.151

EpiControl AF: 0.147

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	0.22
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	19
Dann	Benign	0.53
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.000055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.054
Sift	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.050
ClinPred		0.038	T
GERP RS		1.8
Varity_R		0.15
gMVP		0.018

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: rs12405278; hg19: chr1-152282267; COSMIC: COSV64245576; COSMIC: COSV64245576;