chr1-172659244-GT-G

Variant names:

• chr1-172659244-GT-G
• NM_000639.3:c.44delT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000639.3(FASLG):​c.44delT​(p.Val15GlyfsTer57) variant causes a frameshift 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FASLG NM_000639.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.54

Genes affected

FASLG (HGNC:11936): (Fas ligand) This gene is a member of the tumor necrosis factor superfamily. The primary function of the encoded transmembrane protein is the induction of apoptosis triggered by binding to FAS. The FAS/FASLG signaling pathway is essential for immune system regulation, including activation-induced cell death (AICD) of T cells and cytotoxic T lymphocyte induced cell death. It has also been implicated in the progression of several cancers. Defects in this gene may be related to some cases of systemic lupus erythematosus (SLE). Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-172659244-GT-G is Pathogenic according to our data. Variant chr1-172659244-GT-G is described in ClinVar as [Pathogenic]. Clinvar id is 2765866.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FASLG	NM_000639.3	c.44delT	p.Val15GlyfsTer57	frameshift_variant	Exon 1 of 4	ENST00000367721.3	NP_000630.1
FASLG	NM_001302746.2	c.44delT	p.Val15GlyfsTer57	frameshift_variant	Exon 1 of 3		NP_001289675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FASLG	ENST00000367721.3	c.44delT	p.Val15GlyfsTer57	frameshift_variant	Exon 1 of 4	1	NM_000639.3	ENSP00000356694.2
FASLG	ENST00000340030.4	c.44delT	p.Val15GlyfsTer57	frameshift_variant	Exon 1 of 3	1		ENSP00000344739.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 1 Pathogenic:1

Oct 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Val15Glyfs*57) in the FASLG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FASLG are known to be pathogenic (PMID: 22857792, 25451160). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FASLG-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-172628384;