dbSNP rs397507563: FLG:p.Ser1235HisfsTer211 (chr1-152311183-AC-A) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_002016.2(FLG):c.3702delG(p.Ser1235HisfsTer211) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000269 in 1,612,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

FLG
NM_002016.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: -1.01

Publications

44 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 16 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 169 pathogenic variants in the truncated region.

PP5

Variant 1-152311183-AC-A is Pathogenic according to our data. Variant chr1-152311183-AC-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 50931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.3702delG	p.Ser1235HisfsTer211	frameshift	Exon 3 of 3	NP_002007.1	P20930
CCDST	NR_186761.1		n.578-21397delC		intron	N/A
CCDST	NR_186762.1		n.180-21397delC		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLG	ENST00000368799.2	TSL:1 MANE Select	c.3702delG	p.Ser1235HisfsTer211	frameshift	Exon 3 of 3	ENSP00000357789.1	P20930
CCDST	ENST00000420707.5	TSL:5	n.463-3720delC		intron	N/A
CCDST	ENST00000593011.5	TSL:4	n.377-3720delC		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000146

AC:

AN:

150212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000213

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000207

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000171

AC:

AN:

251482

AF XY:

0.000206

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000282

AC:

412

AN:

1461888

Hom.:

Cov.:

101

AF XY:

0.000292

AC XY:

212

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000536

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000359

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000312

AC:

347

AN:

1112008

Other (OTH)

AF:

0.000298

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

126

157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000146

AC:

AN:

150212

Hom.:

Cov.:

AF XY:

0.000178

AC XY:

AN XY:

73200

show subpopulations

African (AFR)

AF:

0.000147

AC:

AN:

40686

American (AMR)

AF:

0.00

AC:

AN:

15114

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5004

South Asian (SAS)

AF:

0.000213

AC:

AN:

4686

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

306

European-Non Finnish (NFE)

AF:

0.000207

AC:

AN:

67604

Other (OTH)

AF:

0.00

AC:

AN:

2054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.000217

Hom.:

Bravo

AF:

0.000132

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ichthyosis vulgaris (4)

Incidental Discovery (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.0

Mutation Taster

=2/198

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