rs10458360

Variant names:

• chr1-172664835-G-C
• rs10458360
• NM_000639.3:c.451+445G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000639.3(FASLG):​c.451+445G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.561 in 152,100 control chromosomes in the GnomAD database, including 27,265 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (27265 hom., cov: 32)
• Consequence: FASLG NM_000639.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.29
• Publications: 14 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.858 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASLG	NM_000639.3	MANE Select	c.451+445G>C		intron	N/A	NP_000630.1
	FASLG	NM_001302746.2		c.*21+445G>C		intron	N/A	NP_001289675.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASLG	ENST00000367721.3	TSL:1 MANE Select	c.451+445G>C		intron	N/A	ENSP00000356694.2
	FASLG	ENST00000340030.4	TSL:1	c.*21+445G>C		intron	N/A	ENSP00000344739.3

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85251 AN: 151982 Hom.: 27216 Cov.: 32

Gnomad AFR AF: 0.865

Gnomad AMI AF: 0.466

Gnomad AMR AF: 0.491

Gnomad ASJ AF: 0.587

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.710

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.554

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.561 AC: 85350 AN: 152100 Hom.: 27265 Cov.: 32 AF XY: 0.558 AC XY: 41457 AN XY: 74330

African (AFR) AF: 0.865 AC: 35909 AN: 41510

American (AMR) AF: 0.490 AC: 7495 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.587 AC: 2035 AN: 3466

East Asian (EAS) AF: 0.287 AC: 1482 AN: 5156

South Asian (SAS) AF: 0.711 AC: 3426 AN: 4820

European-Finnish (FIN) AF: 0.314 AC: 3312 AN: 10556

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.440 AC: 29900 AN: 67988

Other (OTH) AF: 0.560 AC: 1183 AN: 2114

Alfa AF: 0.481 Hom.: 2949

Bravo AF: 0.581

Asia WGS AF: 0.569 AC: 1978 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.50
DANN	Benign	0.56
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10458360; hg19: chr1-172633975;