1-172659338-C-T
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_000639.3(FASLG):c.137C>T(p.Pro46Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000682 in 1,612,706 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000067 ( 0 hom. )
Consequence
FASLG
NM_000639.3 missense
NM_000639.3 missense
Scores
4
15
Clinical Significance
Conservation
PhyloP100: 2.25
Genes affected
FASLG (HGNC:11936): (Fas ligand) This gene is a member of the tumor necrosis factor superfamily. The primary function of the encoded transmembrane protein is the induction of apoptosis triggered by binding to FAS. The FAS/FASLG signaling pathway is essential for immune system regulation, including activation-induced cell death (AICD) of T cells and cytotoxic T lymphocyte induced cell death. It has also been implicated in the progression of several cancers. Defects in this gene may be related to some cases of systemic lupus erythematosus (SLE). Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2014]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.022909641).
BS2
?
High AC in GnomAd at 12 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FASLG | NM_000639.3 | c.137C>T | p.Pro46Leu | missense_variant | 1/4 | ENST00000367721.3 | |
FASLG | NM_001302746.2 | c.137C>T | p.Pro46Leu | missense_variant | 1/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FASLG | ENST00000367721.3 | c.137C>T | p.Pro46Leu | missense_variant | 1/4 | 1 | NM_000639.3 | P1 | |
FASLG | ENST00000340030.4 | c.137C>T | p.Pro46Leu | missense_variant | 1/3 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152132Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000105 AC: 26AN: 247628Hom.: 0 AF XY: 0.000112 AC XY: 15AN XY: 134248
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GnomAD4 exome AF: 0.0000671 AC: 98AN: 1460574Hom.: 0 Cov.: 32 AF XY: 0.0000895 AC XY: 65AN XY: 726518
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autoimmune lymphoproliferative syndrome type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 14, 2022 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 46 of the FASLG protein (p.Pro46Leu). This variant is present in population databases (rs779382158, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with FASLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 851854). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;D
REVEL
Benign
Sift
Benign
T;D
Sift4G
Uncertain
D;D
Polyphen
B;B
Vest4
MutPred
Loss of glycosylation at P46 (P = 0.0011);Loss of glycosylation at P46 (P = 0.0011);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at