chr10-89010783-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_000043.6(FAS):​c.536T>G​(p.Leu179Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

FAS
NM_000043.6 missense

Scores

1
5
13

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: -0.427
Variant links:
Genes affected
FAS (HGNC:11920): (Fas cell surface death receptor) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor contains a death domain. It has been shown to play a central role in the physiological regulation of programmed cell death, and has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The interaction of this receptor with its ligand allows the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10. The autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, and leads to apoptosis. This receptor has been also shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is found to be involved in transducing the proliferating signals in normal diploid fibroblast and T cells. Several alternatively spliced transcript variants have been described, some of which are candidates for nonsense-mediated mRNA decay (NMD). The isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform. [provided by RefSeq, Mar 2011]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-89010783-T-G is Pathogenic according to our data. Variant chr10-89010783-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.1901528). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FASNM_000043.6 linkc.536T>G p.Leu179Arg missense_variant Exon 6 of 9 ENST00000652046.1 NP_000034.1 P25445-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FASENST00000652046.1 linkc.536T>G p.Leu179Arg missense_variant Exon 6 of 9 NM_000043.6 ENSP00000498466.1 P25445-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Splenomegaly Pathogenic:1
Jan 01, 2017
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:1
Jan 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

FAS: PM2, PP4:Moderate, PS4:Moderate -

Autoimmune lymphoproliferative syndrome type 1 Pathogenic:1
Nov 27, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 179 of the FAS protein (p.Leu179Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autoimmune lymphoproliferative syndrome (ALPS) (internal data). ClinVar contains an entry for this variant (Variation ID: 523313). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FAS protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.57
BayesDel_addAF
Uncertain
0.057
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
14
DANN
Benign
0.72
DEOGEN2
Uncertain
0.56
D;.;.
Eigen
Benign
-0.56
Eigen_PC
Benign
-0.85
FATHMM_MKL
Benign
0.033
N
LIST_S2
Benign
0.62
T;T;T
M_CAP
Benign
0.048
D
MetaRNN
Benign
0.19
T;T;T
MetaSVM
Uncertain
-0.0039
T
MutationAssessor
Benign
1.7
L;.;L
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-2.1
N;N;N
REVEL
Uncertain
0.31
Sift
Benign
0.039
D;D;D
Sift4G
Uncertain
0.0090
D;D;D
Polyphen
0.94
P;.;.
Vest4
0.30
MutPred
0.54
Gain of MoRF binding (P = 0.0075);Gain of MoRF binding (P = 0.0075);Gain of MoRF binding (P = 0.0075);
MVP
0.46
MPC
1.0
ClinPred
0.57
D
GERP RS
0.59
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.48

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.19
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554851718; hg19: chr10-90770540; API