rs121913083

Positions:

• chr10-89008907-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_000043.6(FAS):​c.353A>G​(p.Asn118Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. N118N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FAS NM_000043.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.22

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000043.6
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-89008907-A-G is Pathogenic according to our data. Variant chr10-89008907-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 16511.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAS	NM_000043.6	c.353A>G	p.Asn118Ser	missense_variant	4/9	ENST00000652046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAS	ENST00000652046.1	c.353A>G	p.Asn118Ser	missense_variant	4/9		NM_000043.6	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

SQUAMOUS CELL CARCINOMA, BURN SCAR-RELATED, SOMATIC Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.;.;.
Eigen	Benign	0.097
Eigen_PC	Benign	-0.096
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.54	D;D;D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.1	M;.;M;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.3	D;D;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D
Polyphen		0.99	D;.;D;.
Vest4		0.15
MutPred		0.53		Gain of glycosylation at N118 (P = 0.0279);Gain of glycosylation at N118 (P = 0.0279);Gain of glycosylation at N118 (P = 0.0279);Gain of glycosylation at N118 (P = 0.0279);
MVP		0.89
MPC		0.67
ClinPred		0.93	D
GERP RS		4.2
Varity_R		0.23

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: rs121913083; hg19: chr10-90768664;