rs121913081

chr10-89014251-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000043.6(FAS):c.809C>T(p.Thr270Ile) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T270K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAS NM_000043.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 2.70

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000043.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAS	NM_000043.6	c.809C>T	p.Thr270Ile	missense_variant	9/9	ENST00000652046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAS	ENST00000652046.1	c.809C>T	p.Thr270Ile	missense_variant	9/9		NM_000043.6	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autoimmune lymphoproliferative syndrome, type 1a Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 1999

- -

Autoimmune lymphoproliferative syndrome type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 15, 2023

This variant is not present in population databases (gnomAD no frequency). 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. This variant disrupts the p.Thr270 amino acid residue in FAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10515860, 20935634). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 16506). This variant is also known as T254I. This missense change has been observed in individual(s) with autoimmune lymphoproliferative syndrome and/or clincal features of autoimmune lymphoproliferative syndrome (PMID: 9927496; Invitae). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 270 of the FAS protein (p.Thr270Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	-0.082	T
MutationAssessor	Uncertain	2.9	M;.
MutationTaster	Benign	0.99	A;A;A;A
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.67
MutPred		0.80		Loss of disorder (P = 0.0461);.;
MVP		0.94
MPC		0.82
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs121913081; hg19: chr10-90774008;