1-172665636-A-T

Variant names:

• chr1-172665636-A-T
• rs80358238
• NM_000639.3:c.466A>T

Variant summary

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

The NM_000639.3(FASLG):​c.466A>T​(p.Arg156Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,276 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R156G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FASLG NM_000639.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.530
• Publications: 0 publications found

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]

FASLG Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome type 1

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000639.3. 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
	FASLG	NM_000639.3	MANE Select	c.466A>T	p.Arg156Trp	missense	Exon 4 of 4	NP_000630.1
	FASLG	NM_001302746.2		c.*36A>T		3_prime_UTR	Exon 3 of 3	NP_001289675.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASLG	ENST00000367721.3	TSL:1 MANE Select	c.466A>T	p.Arg156Trp	missense	Exon 4 of 4	ENSP00000356694.2
	FASLG	ENST00000340030.4	TSL:1	c.*36A>T		3_prime_UTR	Exon 3 of 3	ENSP00000344739.3
	FASLG	ENST00000875216.1		c.487A>T	p.Arg163Trp	missense	Exon 4 of 4	ENSP00000545275.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461276 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726980

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	-0.044
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.53
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.22
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.33
MutPred		0.46		Gain of catalytic residue at P159 (P = 0.0213)
MVP		0.52
MPC		0.32
ClinPred		0.97	D
GERP RS		0.98
Varity_R		0.56
gMVP		0.69
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80358238; hg19: chr1-172634776;