dbSNP rs61816761: FLG:p.Arg501* (chr1-152313385-G-A) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 16P and 2B. PVS1PP5_Very_StrongBS1_SupportingBS2_Supporting

The NM_002016.2(FLG):c.1501C>T(p.Arg501*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,613,302 control chromosomes in the GnomAD database, including 315 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.010 ( 17 hom., cov: 30)

Exomes 𝑓: 0.018 ( 298 hom. )

Consequence

FLG
NM_002016.2 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:40O:3

Conservation

PhyloP100: -1.33

Publications

461 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 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 217 pathogenic variants in the truncated region.

PP5

Variant 1-152313385-G-A is Pathogenic according to our data. Variant chr1-152313385-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0104 (1580/151516) while in subpopulation NFE AF = 0.0173 (1176/67888). AF 95% confidence interval is 0.0165. There are 17 homozygotes in GnomAd4. There are 680 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 17 SD,XL,AR,AD 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.1501C>T	p.Arg501*	stop_gained	Exon 3 of 3	NP_002007.1	P20930
CCDST	NR_186761.1		n.578-19198G>A		intron	N/A
CCDST	NR_186762.1		n.180-19198G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLG	ENST00000368799.2	TSL:1 MANE Select	c.1501C>T	p.Arg501*	stop_gained	Exon 3 of 3	ENSP00000357789.1	P20930
CCDST	ENST00000665223.1		n.810G>A		non_coding_transcript_exon	Exon 1 of 5
CCDST	ENST00000420707.5	TSL:5	n.463-1521G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1580

AN:

151398

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00477

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00801

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00105

Gnomad FIN

AF:

0.00180

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0173

Gnomad OTH

AF:

0.00771

GnomAD2 exomes

AF:

0.00937

AC:

2354

AN:

251350

AF XY:

0.00935

show subpopulations

Gnomad AFR exome

AF:

0.00437

Gnomad AMR exome

AF:

0.00396

Gnomad ASJ exome

AF:

0.0121

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00185

Gnomad NFE exome

AF:

0.0166

Gnomad OTH exome

AF:

0.00946

GnomAD4 exome

AF:

0.0176

AC:

25781

AN:

1461786

Hom.:

298

Cov.:

102

AF XY:

0.0171

AC XY:

12440

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.00335

AC:

112

AN:

33466

American (AMR)

AF:

0.00505

AC:

226

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0113

AC:

295

AN:

26132

East Asian (EAS)

AF:

0.000176

AC:

AN:

39700

South Asian (SAS)

AF:

0.00128

AC:

110

AN:

86252

European-Finnish (FIN)

AF:

0.00223

AC:

119

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0216

AC:

24052

AN:

1111950

Other (OTH)

AF:

0.0142

AC:

858

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

2059

4118

6177

8236

10295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

974

1948

2922

3896

4870

<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:

0.0104

AC:

1580

AN:

151516

Hom.:

Cov.:

AF XY:

0.00919

AC XY:

680

AN XY:

73994

show subpopulations

African (AFR)

AF:

0.00475

AC:

196

AN:

41240

American (AMR)

AF:

0.00800

AC:

122

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5090

South Asian (SAS)

AF:

0.00105

AC:

AN:

4758

European-Finnish (FIN)

AF:

0.00180

AC:

AN:

10528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0173

AC:

1176

AN:

67888

Other (OTH)

AF:

0.00763

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

160

241

321

401

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.151

Hom.:

3664

Bravo

AF:

0.0114

TwinsUK

AF:

0.0202

AC:

ALSPAC

AF:

0.0221

AC:

ESP6500AA

AF:

0.00613

AC:

ESP6500EA

AF:

0.0183

AC:

157

ExAC

AF:

0.00873

AC:

1060

EpiCase

AF:

0.0160

EpiControl

AF:

0.0160

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ichthyosis vulgaris (19)

not provided (11)

Dermatitis, atopic, 2 (3)

FLG-related disorder (3)

Ichthyosis vulgaris;C1853965:Dermatitis, atopic, 2 (3)

Atopic eczema;C0079584:Ichthyosis vulgaris (1)

Eczematoid dermatitis (1)

Inborn genetic diseases (1)

Dermatitis, atopic, 2, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Benign

0.97

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.0086

PhyloP100

-1.3

Vest4

0.38

GERP RS

-4.4

Mutation Taster

=4/196

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