1-152302945-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_002016.2(FLG):c.11941A>G(p.Ser3981Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000206 in 1,614,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: FLG NM_002016.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.131

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)

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.038195282).
• BP6: Variant 1-152302945-T-C is Benign according to our data. Variant chr1-152302945-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2358391.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLG	NM_002016.2	c.11941A>G	p.Ser3981Gly	missense_variant	3/3	ENST00000368799.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLG	ENST00000368799.2	c.11941A>G	p.Ser3981Gly	missense_variant	3/3	1	NM_002016.2	P1
FLG-AS1	ENST00000653548.1	n.390-29638T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152198 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000199 AC: 50 AN: 251390 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135856

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000369

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000205 AC: 300 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.000208 AC XY: 151 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000254

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152316 Hom.: 0 Cov.: 31 AF XY: 0.000134 AC XY: 10 AN XY: 74470

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000322 Hom.: 0

Bravo AF: 0.000385

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2022

The c.11941A>G (p.S3981G) alteration is located in exon 3 (coding exon 2) of the FLG gene. This alteration results from a A to G substitution at nucleotide position 11941, causing the serine (S) at amino acid position 3981 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

FLG: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	13
Dann	Benign	0.87
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.046
Sift	Benign	0.13	T
Polyphen		0.97	D
Vest4		0.26
MVP		0.32
ClinPred		0.043	T
GERP RS		2.8
Varity_R		0.041
gMVP		0.0042

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

Other links and lift over

dbSNP: rs201092922; hg19: chr1-152275421;