rs11584340

chr1-152313454-G-Achr1-152313454-G-C

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.1432C>T(p.Pro478Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,613,236 control chromosomes in the GnomAD database, including 42,398 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 0.20 (4073 hom., cov: 29)
  • Exomes 𝑓: 0.20 (38325 hom.)
• Consequence: FLG NM_002016.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.81

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=1.0032969E-5).
• BP6: Variant 1-152313454-G-A is Benign according to our data. Variant chr1-152313454-G-A is described in ClinVar as [Benign]. Clinvar id is 666623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-152313454-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLG	NM_002016.2	c.1432C>T	p.Pro478Ser	missense_variant	3/3	ENST00000368799.2
FLG-AS1	NR_103778.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLG	ENST00000368799.2	c.1432C>T	p.Pro478Ser	missense_variant	3/3	1	NM_002016.2	P1
FLG-AS1	ENST00000653548.1	n.390-19129G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30769 AN: 151304 Hom.: 4065 Cov.: 29

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.592

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.233

GnomAD3 exomes AF: 0.273 AC: 68518 AN: 251380 Hom.: 12341 AF XY: 0.273 AC XY: 37059 AN XY: 135868

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.447

Gnomad ASJ exome AF: 0.304

Gnomad EAS exome AF: 0.579

Gnomad SAS exome AF: 0.424

Gnomad FIN exome AF: 0.179

Gnomad NFE exome AF: 0.165

Gnomad OTH exome AF: 0.253

GnomAD4 exome AF: 0.201 AC: 293476 AN: 1461814 Hom.: 38325 Cov.: 76 AF XY: 0.206 AC XY: 150050 AN XY: 727204

Gnomad4 AFR exome AF: 0.135

Gnomad4 AMR exome AF: 0.437

Gnomad4 ASJ exome AF: 0.303

Gnomad4 EAS exome AF: 0.606

Gnomad4 SAS exome AF: 0.411

Gnomad4 FIN exome AF: 0.177

Gnomad4 NFE exome AF: 0.159

Gnomad4 OTH exome AF: 0.237

GnomAD4 genome AF: 0.203 AC: 30790 AN: 151422 Hom.: 4073 Cov.: 29 AF XY: 0.215 AC XY: 15863 AN XY: 73952

Gnomad4 AFR AF: 0.138

Gnomad4 AMR AF: 0.358

Gnomad4 ASJ AF: 0.314

Gnomad4 EAS AF: 0.592

Gnomad4 SAS AF: 0.434

Gnomad4 FIN AF: 0.187

Gnomad4 NFE AF: 0.159

Gnomad4 OTH AF: 0.230

Alfa AF: 0.172 Hom.: 1495

Bravo AF: 0.215

TwinsUK AF: 0.158 AC: 586

ALSPAC AF: 0.163 AC: 629

ESP6500AA AF: 0.140 AC: 615

ESP6500EA AF: 0.168 AC: 1444

ExAC AF: 0.261 AC: 31705

Asia WGS AF: 0.507 AC: 1761 AN: 3478

EpiCase AF: 0.175

EpiControl AF: 0.171

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 23, 2016

p.Pro478Ser in exon 3 of FLG: This variant is not expected to have clinical sign ificance because it has been identified in 58.20% (5010/8608) of East Asian chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs11584340). -

Ichthyosis vulgaris Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2020

This variant is associated with the following publications: (PMID: 21219289, 25458912, 18193244, 24521637) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.0060
Dann	Benign	0.67
DEOGEN2	Benign	0.018	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.00021	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.000010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.6	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.042
Sift	Benign	1.0	T
Polyphen		0.020	B
Vest4		0.010
ClinPred		0.0078	T
GERP RS		-3.1
Varity_R		0.023
gMVP		0.048

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: rs11584340; hg19: chr1-152285930; COSMIC: COSV64239594; COSMIC: COSV64239594;