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GeneBe

1-152303006-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_002016.2(FLG):c.11880T>C(p.Ser3960=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00033 in 1,614,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

FLG
NM_002016.2 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.86
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-AS1 (HGNC:27913): (cervical cancer associated DHX9 suppressive transcript)

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-152303006-A-G is Benign according to our data. Variant chr1-152303006-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2639221.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-1.86 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FLGNM_002016.2 linkuse as main transcriptc.11880T>C p.Ser3960= synonymous_variant 3/3 ENST00000368799.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FLGENST00000368799.2 linkuse as main transcriptc.11880T>C p.Ser3960= synonymous_variant 3/31 NM_002016.2 P1
FLG-AS1ENST00000653548.1 linkuse as main transcriptn.390-29577A>G intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000631
AC:
96
AN:
152168
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000700
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00216
Gnomad ASJ
AF:
0.00317
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000265
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.000497
AC:
125
AN:
251398
Hom.:
0
AF XY:
0.000405
AC XY:
55
AN XY:
135860
show subpopulations
Gnomad AFR exome
AF:
0.000677
Gnomad AMR exome
AF:
0.00110
Gnomad ASJ exome
AF:
0.00357
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000196
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000264
Gnomad OTH exome
AF:
0.000652
GnomAD4 exome
AF:
0.000298
AC:
435
AN:
1461890
Hom.:
0
Cov.:
31
AF XY:
0.000285
AC XY:
207
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00173
Gnomad4 AMR exome
AF:
0.00107
Gnomad4 ASJ exome
AF:
0.00348
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000151
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000142
Gnomad4 OTH exome
AF:
0.000993
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000637
AC:
97
AN:
152286
Hom.:
0
Cov.:
31
AF XY:
0.000739
AC XY:
55
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.000722
Gnomad4 AMR
AF:
0.00216
Gnomad4 ASJ
AF:
0.00317
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000265
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.000625
Hom.:
0
Bravo
AF:
0.000650
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.000327
EpiControl
AF:
0.000711

ClinVar

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

Submissions by phenotype

not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2023FLG: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
Cadd
Benign
0.37
Dann
Benign
0.48

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs144643375; hg19: chr1-152275482; API