Genetic Variant FLG:p.Ser3247* (chr1-152305146-G-T) – ACMG Classification: Pathogenic (19 pts)

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 20P and 1B. PVS1PS3PP5_Very_StrongBS2_Supporting

The NM_002016.2(FLG):c.9740C>A(p.Ser3247*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00279 in 1,613,830 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002038527: Oji et al. (2009) evaluated the structure, histology, and antigen mapping using immunofluorescence of skin samples from an individual with ichthyosis vulgaris with the variant in heterozygous state. Filaggrin antigen was reduced and the stratum granulosum was reduced, but focally normal. PMID:20026562".

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 30)

Exomes 𝑓: 0.0029 ( 15 hom. )

Consequence

FLG
NM_002016.2 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17O:1

Conservation

PhyloP100: -0.595

Publications

179 publications found

Variant links:

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 links:

CCDST (HGNC:55988): (cervical cancer associated DHX9 suppressive transcript)

CCDST links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 40 pathogenic variants in the truncated region.

PS3

PS3 evidence extracted from ClinVar submissions: SCV002038527: Oji et al. (2009) evaluated the structure, histology, and antigen mapping using immunofluorescence of skin samples from an individual with ichthyosis vulgaris with the variant in heterozygous state. Filaggrin antigen was reduced and the stratum granulosum was reduced, but focally normal. PMID:20026562

PP5

Variant 1-152305146-G-T is Pathogenic according to our data. Variant chr1-152305146-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 50930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 15 AD,XL,AR,SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002016.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLG	NM_002016.2	MANE Select	c.9740C>A	p.Ser3247*	stop_gained	Exon 3 of 3	NP_002007.1	P20930
CCDST	NR_186761.1		n.578-27437G>T		intron	N/A
CCDST	NR_186762.1		n.180-27437G>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLG	ENST00000368799.2	TSL:1 MANE Select	c.9740C>A	p.Ser3247*	stop_gained	Exon 3 of 3	ENSP00000357789.1	P20930
CCDST	ENST00000420707.5	TSL:5	n.462+3313G>T		intron	N/A
CCDST	ENST00000593011.5	TSL:4	n.376+3313G>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00157

AC:

238

AN:

151886

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000677

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00288

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00148

AC:

372

AN:

251454

AF XY:

0.00150

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000693

Gnomad NFE exome

AF:

0.00286

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00292

AC:

4270

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00280

AC XY:

2039

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33480

American (AMR)

AF:

0.000268

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.000599

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00357

AC:

3975

AN:

1111984

Other (OTH)

AF:

0.00386

AC:

233

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

381

762

1143

1524

1905

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

162

324

486

648

810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00157

AC:

238

AN:

152002

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

103

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.000675

AC:

AN:

41494

American (AMR)

AF:

0.000590

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5140

South Asian (SAS)

AF:

0.00

AC:

AN:

4778

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00288

AC:

196

AN:

67942

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00127

Hom.:

Bravo

AF:

0.00172

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00135

AC:

164

EpiCase

AF:

0.00365

EpiControl

AF:

0.00284

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ichthyosis vulgaris (8)

not provided (6)

Dermatitis, atopic, 2 (1)

FLG-related disorder (1)

See cases (1)

Ichthyosis vulgaris;C1853965:Dermatitis, atopic, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Benign

0.97

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.038

PhyloP100

-0.59

Vest4

0.34

GERP RS

-0.016

Mutation Taster

=21/179

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over