chr1-152309791-G-A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_002016.2(FLG):​c.5095C>T​(p.Arg1699Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,613,668 control chromosomes in the GnomAD database, including 33,339 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1699H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.16 ( 3131 hom., cov: 30)
Exomes 𝑓: 0.17 ( 30208 hom. )

Consequence

FLG
NM_002016.2 missense

Scores

1
16

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0710

Publications

29 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]
CCDST (HGNC:55988): (cervical cancer associated DHX9 suppressive transcript)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=5.5109176E-5).
BP6
Variant 1-152309791-G-A is Benign according to our data. Variant chr1-152309791-G-A is described in ClinVar as [Benign]. Clinvar id is 2585649.Status of the report is criteria_provided_single_submitter, 1 stars.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.552 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FLGNM_002016.2 linkc.5095C>T p.Arg1699Cys missense_variant Exon 3 of 3 ENST00000368799.2 NP_002007.1 P20930

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FLGENST00000368799.2 linkc.5095C>T p.Arg1699Cys missense_variant Exon 3 of 3 1 NM_002016.2 ENSP00000357789.1 P20930

Frequencies

GnomAD3 genomes
AF:
0.157
AC:
23815
AN:
151676
Hom.:
3128
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0341
Gnomad AMI
AF:
0.156
Gnomad AMR
AF:
0.326
Gnomad ASJ
AF:
0.293
Gnomad EAS
AF:
0.570
Gnomad SAS
AF:
0.377
Gnomad FIN
AF:
0.180
Gnomad MID
AF:
0.215
Gnomad NFE
AF:
0.135
Gnomad OTH
AF:
0.196
GnomAD2 exomes
AF:
0.242
AC:
60910
AN:
251468
AF XY:
0.242
show subpopulations
Gnomad AFR exome
AF:
0.0290
Gnomad AMR exome
AF:
0.428
Gnomad ASJ exome
AF:
0.280
Gnomad EAS exome
AF:
0.560
Gnomad FIN exome
AF:
0.171
Gnomad NFE exome
AF:
0.142
Gnomad OTH exome
AF:
0.227
GnomAD4 exome
AF:
0.173
AC:
252819
AN:
1461874
Hom.:
30208
Cov.:
81
AF XY:
0.178
AC XY:
129266
AN XY:
727242
show subpopulations
African (AFR)
AF:
0.0265
AC:
888
AN:
33480
American (AMR)
AF:
0.417
AC:
18662
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.279
AC:
7297
AN:
26136
East Asian (EAS)
AF:
0.561
AC:
22282
AN:
39698
South Asian (SAS)
AF:
0.356
AC:
30708
AN:
86256
European-Finnish (FIN)
AF:
0.167
AC:
8942
AN:
53420
Middle Eastern (MID)
AF:
0.247
AC:
1422
AN:
5768
European-Non Finnish (NFE)
AF:
0.135
AC:
150177
AN:
1111996
Other (OTH)
AF:
0.206
AC:
12441
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.470
Heterozygous variant carriers
0
14075
28150
42224
56299
70374
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
5816
11632
17448
23264
29080
<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:
0.157
AC:
23815
AN:
151794
Hom.:
3131
Cov.:
30
AF XY:
0.168
AC XY:
12488
AN XY:
74166
show subpopulations
African (AFR)
AF:
0.0341
AC:
1411
AN:
41428
American (AMR)
AF:
0.327
AC:
4991
AN:
15260
Ashkenazi Jewish (ASJ)
AF:
0.293
AC:
1014
AN:
3466
East Asian (EAS)
AF:
0.570
AC:
2890
AN:
5074
South Asian (SAS)
AF:
0.375
AC:
1796
AN:
4784
European-Finnish (FIN)
AF:
0.180
AC:
1896
AN:
10550
Middle Eastern (MID)
AF:
0.224
AC:
65
AN:
290
European-Non Finnish (NFE)
AF:
0.136
AC:
9204
AN:
67926
Other (OTH)
AF:
0.193
AC:
406
AN:
2106
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.499
Heterozygous variant carriers
0
916
1832
2749
3665
4581
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
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:
0.152
Hom.:
7402
Bravo
AF:
0.166
TwinsUK
AF:
0.136
AC:
504
ALSPAC
AF:
0.137
AC:
527
ESP6500AA
AF:
0.0365
AC:
161
ESP6500EA
AF:
0.144
AC:
1240
ExAC
AF:
0.229
AC:
27771
Asia WGS
AF:
0.455
AC:
1581
AN:
3478
EpiCase
AF:
0.151
EpiControl
AF:
0.147

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Ichthyosis vulgaris Benign:1
Apr 11, 2023
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Benign
-0.78
T
BayesDel_noAF
Benign
-0.75
CADD
Benign
19
DANN
Benign
0.53
DEOGEN2
Benign
0.032
T
Eigen
Benign
-0.53
Eigen_PC
Benign
-0.78
FATHMM_MKL
Benign
0.029
N
LIST_S2
Benign
0.63
T
MetaRNN
Benign
0.000055
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.7
L
PhyloP100
-0.071
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-2.3
N
REVEL
Benign
0.054
Sift
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.050
ClinPred
0.038
T
GERP RS
1.8
Varity_R
0.15
gMVP
0.018
Mutation Taster
=100/0
polymorphism (auto)

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

Other links and lift over

dbSNP: rs12405278; hg19: chr1-152282267; COSMIC: COSV64245576; COSMIC: COSV64245576; API