chr1-172659338-C-A

Variant names:

• chr1-172659338-C-A
• rs779382158
• NM_000639.3:c.137C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000639.3(FASLG):​c.137C>A​(p.Pro46Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. P46L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FASLG NM_000639.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.25

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2243559).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FASLG	NM_000639.3	c.137C>A	p.Pro46Gln	missense_variant	Exon 1 of 4	ENST00000367721.3	NP_000630.1
FASLG	NM_001302746.2	c.137C>A	p.Pro46Gln	missense_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.137C>A	p.Pro46Gln	missense_variant	Exon 1 of 4	1	NM_000639.3	ENSP00000356694.2
FASLG	ENST00000340030.4	c.137C>A	p.Pro46Gln	missense_variant	Exon 1 of 3	1		ENSP00000344739.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460574 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726518

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.46	N;D
REVEL	Benign	0.083
Sift	Benign	0.45	T;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.98	D;D
Vest4		0.43
MutPred		0.34		Loss of glycosylation at P46 (P = 0.0011);Loss of glycosylation at P46 (P = 0.0011);
MVP		0.53
MPC		0.55
ClinPred		0.68	D
GERP RS		3.6
Varity_R		0.039
gMVP		0.14

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: rs779382158; hg19: chr1-172628478;