dbSNP rs151103850: FLG:p.Arg1560Cys (chr1-152310208-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002016.2(FLG):c.4678C>T(p.Arg1560Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0394 in 1,613,778 control chromosomes in the GnomAD database, including 1,536 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 104 hom., cov: 30)

Exomes 𝑓: 0.040 ( 1432 hom. )

Consequence

FLG
NM_002016.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.56

Publications

7 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029270947).

BP6

Variant 1-152310208-G-A is Benign according to our data. Variant chr1-152310208-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 402868.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 = 0.0297 (4509/151892) while in subpopulation NFE AF = 0.0435 (2954/67960). AF 95% confidence interval is 0.0422. There are 104 homozygotes in GnomAd4. There are 2189 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 104 SD,XL,AR,AD gene

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.4678C>T	p.Arg1560Cys	missense	Exon 3 of 3	NP_002007.1	P20930
CCDST	NR_186761.1		n.578-22375G>A		intron	N/A
CCDST	NR_186762.1		n.180-22375G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLG	ENST00000368799.2	TSL:1 MANE Select	c.4678C>T	p.Arg1560Cys	missense	Exon 3 of 3	ENSP00000357789.1	P20930
CCDST	ENST00000420707.5	TSL:5	n.463-4698G>A		intron	N/A
CCDST	ENST00000593011.5	TSL:4	n.377-4698G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0297

AC:

4509

AN:

151774

Hom.:

104

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00791

Gnomad AMI

AF:

0.0198

Gnomad AMR

AF:

0.0242

Gnomad ASJ

AF:

0.0622

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.0119

Gnomad FIN

AF:

0.0486

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0435

Gnomad OTH

AF:

0.0245

GnomAD2 exomes

AF:

0.0310

AC:

7792

AN:

251470

AF XY:

0.0312

show subpopulations

Gnomad AFR exome

AF:

0.00621

Gnomad AMR exome

AF:

0.0156

Gnomad ASJ exome

AF:

0.0591

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0524

Gnomad NFE exome

AF:

0.0427

Gnomad OTH exome

AF:

0.0332

GnomAD4 exome

AF:

0.0404

AC:

59123

AN:

1461886

Hom.:

1432

Cov.:

AF XY:

0.0398

AC XY:

28937

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00591

AC:

198

AN:

33480

American (AMR)

AF:

0.0164

AC:

733

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0600

AC:

1569

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39698

South Asian (SAS)

AF:

0.0137

AC:

1186

AN:

86258

European-Finnish (FIN)

AF:

0.0539

AC:

2877

AN:

53420

Middle Eastern (MID)

AF:

0.00988

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0452

AC:

50264

AN:

1112006

Other (OTH)

AF:

0.0370

AC:

2234

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

4367

8734

13100

17467

21834

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1844

3688

5532

7376

9220

<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:

0.0297

AC:

4509

AN:

151892

Hom.:

104

Cov.:

AF XY:

0.0295

AC XY:

2189

AN XY:

74220

show subpopulations

African (AFR)

AF:

0.00789

AC:

327

AN:

41452

American (AMR)

AF:

0.0241

AC:

368

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.0622

AC:

216

AN:

3470

East Asian (EAS)

AF:

0.000196

AC:

AN:

5114

South Asian (SAS)

AF:

0.0121

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.0486

AC:

513

AN:

10548

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0435

AC:

2954

AN:

67960

Other (OTH)

AF:

0.0242

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

199

398

597

796

995

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0369

Hom.:

134

Bravo

AF:

0.0268

TwinsUK

AF:

0.0496

AC:

184

ALSPAC

AF:

0.0475

AC:

183

ESP6500AA

AF:

0.00704

AC:

ESP6500EA

AF:

0.0410

AC:

353

ExAC

AF:

0.0307

AC:

3722

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0414

EpiControl

AF:

0.0398

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ichthyosis vulgaris (2)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.83

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.049

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.64

MetaRNN

Benign

0.0029

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.3

PhyloP100

-2.6

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.1

REVEL

Benign

0.084

Sift

Benign

0.068

Polyphen

0.98

Vest4

0.031

ClinPred

0.024

GERP RS

0.34

Varity_R

0.057

gMVP

0.020

Mutation Taster

=100/0

polymorphism (auto)

(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