10-89014191-G-C

Position:

• chr10-89014191-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000043.6(FAS):​c.749G>C​(p.Arg250Pro) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R250Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAS NM_000043.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:4
• Conservation: PhyloP100: 5.27

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a domain Death (size 84) in uniprot entity TNR6_HUMAN there are 17 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, 0.993
• PP5: Variant 10-89014191-G-C is Pathogenic according to our data. Variant chr10-89014191-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 16505.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-89014191-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAS	NM_000043.6	c.749G>C	p.Arg250Pro	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.749G>C	p.Arg250Pro	missense_variant	9/9		NM_000043.6	ENSP00000498466.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Autoimmune lymphoproliferative syndrome type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 25, 2023

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 250 of the FAS protein (p.Arg250Pro). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg250 amino acid residue in FAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10090885, 18948840, 21490157). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects FAS function (PMID: 9927496, 10090885, 21490157). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FAS protein function. ClinVar contains an entry for this variant (Variation ID: 16505). This variant is also known as c.943G>C (p.R234P). This variant has been observed in individual(s) with autoimmue lymphoproliferative syndrome (PMID: 10090885). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). -

Autoimmune lymphoproliferative syndrome, type 1a Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.82
MutPred		0.93		Loss of MoRF binding (P = 0.007);.;
MVP		0.99
MPC		1.0
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.98

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: rs121913080; hg19: chr10-90773948;