Genetic Variant NM_002016.2:c.10017G>A (chr1-152304869-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_002016.2(FLG):c.10017G>A(p.Gln3339Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,613,646 control chromosomes in the GnomAD database, including 33,854 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.16 ( 3149 hom., cov: 29)

Exomes 𝑓: 0.17 ( 30705 hom. )

Consequence

FLG
NM_002016.2 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.308

Publications

20 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: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 1-152304869-C-T is Benign according to our data. Variant chr1-152304869-C-T is described in ClinVar as Benign. ClinVar VariationId is 2585647.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.308 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

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.10017G>A	p.Gln3339Gln	synonymous	Exon 3 of 3	NP_002007.1	P20930
CCDST	NR_186761.1		n.578-27714C>T		intron	N/A
CCDST	NR_186762.1		n.180-27714C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLG	ENST00000368799.2	TSL:1 MANE Select	c.10017G>A	p.Gln3339Gln	synonymous	Exon 3 of 3	ENSP00000357789.1	P20930
CCDST	ENST00000420707.5	TSL:5	n.462+3036C>T		intron	N/A
CCDST	ENST00000593011.5	TSL:4	n.376+3036C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.157

AC:

23751

AN:

151688

Hom.:

3146

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0340

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.326

Gnomad ASJ

AF:

0.292

Gnomad EAS

AF:

0.567

Gnomad SAS

AF:

0.378

Gnomad FIN

AF:

0.178

Gnomad MID

AF:

0.222

Gnomad NFE

AF:

0.135

Gnomad OTH

AF:

0.195

GnomAD2 exomes

AF:

0.243

AC:

61072

AN:

251484

AF XY:

0.243

show subpopulations

Gnomad AFR exome

AF:

0.0290

Gnomad AMR exome

AF:

0.429

Gnomad ASJ exome

AF:

0.281

Gnomad EAS exome

AF:

0.560

Gnomad FIN exome

AF:

0.171

Gnomad NFE exome

AF:

0.142

Gnomad OTH exome

AF:

0.228

GnomAD4 exome

AF:

0.173

AC:

253172

AN:

1461840

Hom.:

30705

Cov.:

AF XY:

0.178

AC XY:

129525

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.0265

AC:

888

AN:

33480

American (AMR)

AF:

0.418

AC:

18697

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.280

AC:

7314

AN:

26136

East Asian (EAS)

AF:

0.560

AC:

22219

AN:

39700

South Asian (SAS)

AF:

0.359

AC:

30967

AN:

86236

European-Finnish (FIN)

AF:

0.168

AC:

8970

AN:

53420

Middle Eastern (MID)

AF:

0.250

AC:

1440

AN:

5766

European-Non Finnish (NFE)

AF:

0.135

AC:

150220

AN:

1111990

Other (OTH)

AF:

0.206

AC:

12457

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

16096

32192

48288

64384

80480

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5812

11624

17436

23248

29060

<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:

0.156

AC:

23751

AN:

151806

Hom.:

3149

Cov.:

AF XY:

0.168

AC XY:

12443

AN XY:

74136

show subpopulations

African (AFR)

AF:

0.0339

AC:

1408

AN:

41500

American (AMR)

AF:

0.327

AC:

4987

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.292

AC:

1013

AN:

3468

East Asian (EAS)

AF:

0.566

AC:

2857

AN:

5048

South Asian (SAS)

AF:

0.377

AC:

1795

AN:

4758

European-Finnish (FIN)

AF:

0.178

AC:

1872

AN:

10518

Middle Eastern (MID)

AF:

0.231

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.135

AC:

9204

AN:

67956

Other (OTH)

AF:

0.192

AC:

405

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

835

1670

2506

3341

4176

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

258

516

774

1032

1290

<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:

0.141

Hom.:

887

Bravo

AF:

0.166

Asia WGS

AF:

0.455

AC:

1579

AN:

3476

EpiCase

AF:

0.151

EpiControl

AF:

0.148

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ichthyosis vulgaris (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.37

(source)

DANN

Benign

0.32

PhyloP100

-0.31

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