rs80358237
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000639.3(FASLG):c.740C>A(p.Ala247Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,611,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_000639.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250692Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135468
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459434Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 725554
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74318
ClinVar
Submissions by phenotype
Autoimmune lymphoproliferative syndrome type 1 Uncertain:1Other:1
This patient developed peripheral T-cell lymphoma -
This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 247 of the FASLG protein (p.Ala247Glu). This variant is present in population databases (rs80358237, gnomAD 0.0009%). This missense change has been observed in individual(s) with autoimmune lymphoproliferative syndrome (ALPS) (PMID: 16627752). ClinVar contains an entry for this variant (Variation ID: 1327543). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FASLG protein function. Experimental studies have shown that this missense change affects FASLG function (PMID: 21368861). 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at