rs121913076

Positions:

• chr10-89014163-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_000043.6(FAS):​c.721A>C​(p.Thr241Pro) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T241K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAS NM_000043.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.21

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 9 ACMG points.

• PM1: In a region_of_interest Interaction with CALM (size 24) in uniprot entity TNR6_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) 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, 0.919
• PP5: Variant 10-89014163-A-C is Pathogenic according to our data. Variant chr10-89014163-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 16499.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAS	NM_000043.6	c.721A>C	p.Thr241Pro	missense_variant	9/9	ENST00000652046.1	NP_000034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046.1	c.721A>C	p.Thr241Pro	missense_variant	9/9		NM_000043.6	ENSP00000498466	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autoimmune lymphoproliferative syndrome, type 1a Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 16, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Uncertain	0.12
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.67	D;.
Eigen	Benign	-0.013
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.57	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.013	D
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	0.82	A;A;A;A
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.69
Sift	Benign	0.068	T;D
Sift4G	Benign	0.11	T;T
Polyphen		0.97	D;D
Vest4		0.32
MutPred		0.87		Gain of loop (P = 0.0166);.;
MVP		0.97
MPC		0.82
ClinPred		0.95	D
GERP RS		3.6
Varity_R		0.92

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: rs121913076; hg19: chr10-90773920;