rs121913079

chr10-89014137-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000043.6(FAS):c.695A>G(p.Tyr232Cys) variant causes a missense change. 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. Y232H) has been classified as Uncertain significance.

• 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: 4.89

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 6 ACMG points.

• PM1: In a helix (size 10) in uniprot entity TNR6_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000043.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAS	NM_000043.6	c.695A>G	p.Tyr232Cys	missense_variant	9/9	ENST00000652046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAS	ENST00000652046.1	c.695A>G	p.Tyr232Cys	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, 1997

- -

Autoimmune lymphoproliferative syndrome type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 22, 2018

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. Experimental studies have shown that this missense change interferes with the function of Fas protein (PMID: 20935634, 26942442). This variant has been observed to segregate with autoimmune lymphoproliferative syndrome in a family (PMID: 9028321). ClinVar contains an entry for this variant (Variation ID: 16503). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosin with cysteine at codon 232 of the FAS protein (p.Tyr232Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosin and cysteine -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;.
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	2.3e-8	A;A;A;A
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.4	D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.44
MutPred		0.90		Gain of methylation at K231 (P = 0.029);.;
MVP		0.99
MPC		0.88
ClinPred		0.77	D
GERP RS		4.8
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: rs121913079; hg19: chr10-90773894;