rs56006128
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2
The NM_000043.6(FAS):c.580G>A(p.Glu194Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,613,886 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000043.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FAS | NM_000043.6 | c.580G>A | p.Glu194Lys | missense_variant | 7/9 | ENST00000652046.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FAS | ENST00000652046.1 | c.580G>A | p.Glu194Lys | missense_variant | 7/9 | NM_000043.6 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00142 AC: 216AN: 152188Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00154 AC: 388AN: 251260Hom.: 1 AF XY: 0.00182 AC XY: 247AN XY: 135814
GnomAD4 exome AF: 0.00177 AC: 2589AN: 1461580Hom.: 4 Cov.: 30 AF XY: 0.00186 AC XY: 1350AN XY: 727110
GnomAD4 genome ? AF: 0.00142 AC: 216AN: 152306Hom.: 0 Cov.: 33 AF XY: 0.00138 AC XY: 103AN XY: 74474
ClinVar
Submissions by phenotype
Autoimmune lymphoproliferative syndrome type 1 Uncertain:3Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 17, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 06, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | FAS NM_000043.5 exon7 p.Glu194Lys (c.580G>A): This variant has been reported in the literature in at least one individual with autoimmune lymphoproliferative syndrome (ALPS)(Campagnoli 2006 PMID:16537120, Boggio 2013 PMID:24043286). This variant is present in 0.2% (306/126586) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/dbsnp/rs56006128). This variant is present in ClinVar (Variation ID:134374). Evolutionary conservation and computational predictive tools for this variant are unclear. In vitro functional studies suggest that this variant will impact the protein (Boggio 2013 PMID:24043286). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
not provided Uncertain:1Benign:4
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 08, 2018 | The E194K variant in the FAS gene has been reported previously in association with autoimmune lymphoproliferative syndrome type 1A (Campagnoli et al., 2006; Rao et al., 2009). The E194K variant is observed in 306/126,586 (0.24%) alleles from individuals of non-Finnish European background and 414/277,020 (0.15%) total alleles, including one homozygous individual, in large population cohorts (Lek et al., 2016). The E194K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies have shown that E194K decreases the function of the FAS protein (Boggio et al., 2013). We interpret E194K as a variant of uncertain significance. - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | FAS: BP4, BS1 - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Uncertain:1Benign:1Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 23, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 14, 2017 | - - |
FAS-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 26, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at