rs376383896
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_000639.3(FASLG):c.394+3G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,613,884 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 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000063 ( 0 hom. )
Consequence
FASLG
NM_000639.3 splice_donor_region, intron
NM_000639.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.00003746
2
Clinical Significance
Conservation
PhyloP100: 0.532
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 Likely_benign. Variant got -6 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.38).
BS2
?
High AC in GnomAd at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FASLG | NM_000639.3 | c.394+3G>A | splice_donor_region_variant, intron_variant | ENST00000367721.3 | |||
FASLG | NM_001302746.2 | c.348+594G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FASLG | ENST00000367721.3 | c.394+3G>A | splice_donor_region_variant, intron_variant | 1 | NM_000639.3 | P1 | |||
FASLG | ENST00000340030.4 | c.348+594G>A | intron_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152188Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000716 AC: 18AN: 251434Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135884
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GnomAD4 exome AF: 0.0000629 AC: 92AN: 1461696Hom.: 0 Cov.: 30 AF XY: 0.0000619 AC XY: 45AN XY: 727170
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GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74352
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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 | Oct 03, 2023 | This sequence change falls in intron 2 of the FASLG gene. It does not directly change the encoded amino acid sequence of the FASLG protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs376383896, gnomAD 0.01%). 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: 574003). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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
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Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at