10-89008986-C-G

Variant names:

• chr10-89008986-C-G
• rs574338716
• NM_000043.6:c.432C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000043.6(FAS):​c.432C>G​(p.Asp144Glu) 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 benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D144N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FAS NM_000043.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.25
• Publications: 3 publications found

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]

FAS Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome type 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autoimmune lymphoproliferative syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08337012).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000043.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	NM_000043.6	MANE Select	c.432C>G	p.Asp144Glu	missense	Exon 4 of 9	NP_000034.1	P25445-1
	FAS	NM_001410956.1		c.477C>G	p.Asp159Glu	missense	Exon 4 of 9	NP_001397885.1	A0A8Q3SIR6
	FAS	NM_152871.4		c.432C>G	p.Asp144Glu	missense	Exon 4 of 8	NP_690610.1	P25445-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	ENST00000652046.1	MANE Select	c.432C>G	p.Asp144Glu	missense	Exon 4 of 9	ENSP00000498466.1	P25445-1
	FAS	ENST00000357339.7	TSL:1	c.432C>G	p.Asp144Glu	missense	Exon 4 of 8	ENSP00000349896.2	P25445-6
	FAS	ENST00000355279.2	TSL:1	c.432C>G	p.Asp144Glu	missense	Exon 4 of 8	ENSP00000347426.2	P25445-7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	7.9
DANN	Benign	0.78
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.4	L
PhyloP100		-2.3
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.16
Sift	Benign	0.28	T
Sift4G	Benign	0.24	T
Polyphen		0.097	B
Vest4		0.075
MutPred		0.26		Gain of ubiquitination at K148 (P = 0.0964)
MVP		0.61
MPC		0.24
ClinPred		0.10	T
GERP RS		-0.17
Varity_R		0.15
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs574338716; hg19: chr10-90768743;