10-89012083-T-C

Variant names:

• chr10-89012083-T-C
• rs267607122
• NM_000043.6:c.651+2T>C

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000043.6(FAS):​c.651+2T>C variant causes a splice donor, intron 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. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001580908: RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. Studies have shown that disruption of this splice site results in skipping of exon 7 and introduces a premature termination codon (PMID:15459303).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAS NM_000043.6 splice_donor, intron
• Scores: Splicing: ADA: 0.9375
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.57
• Publications: 5 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: Pathogenic. The variant received 22 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 8.3, offset of 4, new splice context is: cagGTattg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001580908: RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. Studies have shown that disruption of this splice site results in skipping of exon 7 and introduces a premature termination codon (PMID: 15459303).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-89012083-T-C is Pathogenic according to our data. Variant chr10-89012083-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 16514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.651+2T>C		splice_donor intron	N/A	NP_000034.1	P25445-1
	FAS	NM_001410956.1		c.696+2T>C		splice_donor intron	N/A	NP_001397885.1	A0A8Q3SIR6
	FAS	NM_152871.4		c.588+2T>C		splice_donor intron	N/A	NP_690610.1	P25445-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	ENST00000652046.1	MANE Select	c.651+2T>C		splice_donor intron	N/A	ENSP00000498466.1	P25445-1
	FAS	ENST00000357339.7	TSL:1	c.588+2T>C		splice_donor intron	N/A	ENSP00000349896.2	P25445-6
	FAS	ENST00000355279.2	TSL:1	c.651+2T>C		splice_donor intron	N/A	ENSP00000347426.2	P25445-7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Autoimmune lymphoproliferative syndrome type 1 (2)
1	-	-	AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IA (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	33
DANN	Benign	0.95
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		2.6
ClinPred		0.93	D
GERP RS		3.3
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Benign	0.52
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.83		Position offset: 2
DS_DL_spliceai		0.76		Position offset: -2

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

Other links and lift over

dbSNP: rs267607122; hg19: chr10-90771840; COSMIC: COSV58238150; COSMIC: COSV58238150;