chr10-89012010-G-A
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
Ensembl
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
not provided Uncertain:2Benign:4
Reported previously in association with autoimmune lymphoproliferative syndrome type 1A (PMID: 16537120, 19214977, 32441320, 33838017, 36844186); Functional studies have shown that E194K decreases the function of the FAS protein (PMID: 24043286); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27153395, 27884173, 24728327, 19214977, 31172514, 31939527, 36268024, 32441320, 33838017, 36844186, 35741048, 16537120, 24043286) -
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FAS: BP4, BS1 -
BS1, BS2, PS4_moderate -
Autoimmune lymphoproliferative syndrome type 1 Uncertain:3Benign:2
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. -
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
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. -
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not specified Uncertain:1Benign:1Other:1
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FAS-related disorder Benign:1
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