1-172659342-A-ACCACCG

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000639.3(FASLG):c.153_158dup(p.Pro52_Pro53dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000388 in 1,610,614 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: FASLG NM_000639.3 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.54

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_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASLG	NM_000639.3	c.153_158dup	p.Pro52_Pro53dup	inframe_insertion	1/4	ENST00000367721.3
FASLG	NM_001302746.2	c.153_158dup	p.Pro52_Pro53dup	inframe_insertion	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASLG	ENST00000367721.3	c.153_158dup	p.Pro52_Pro53dup	inframe_insertion	1/4	1	NM_000639.3	P1
FASLG	ENST00000340030.4	c.153_158dup	p.Pro52_Pro53dup	inframe_insertion	1/3	1

Frequencies

GnomAD3 genomes AF: 0.000231 AC: 35 AN: 151750 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000962

GnomAD3 exomes AF: 0.000192 AC: 47 AN: 244282 Hom.: 0 AF XY: 0.000211 AC XY: 28 AN XY: 132564

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.000176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000337

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000404 AC: 590 AN: 1458864 Hom.: 0 Cov.: 32 AF XY: 0.000411 AC XY: 298 AN XY: 725636

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000180

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000504

Gnomad4 OTH exome AF: 0.000283

GnomAD4 genome AF: 0.000231 AC: 35 AN: 151750 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74110

Gnomad4 AFR AF: 0.0000727

Gnomad4 AMR AF: 0.000394

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.000962

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FASLG-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 06, 2023

The FASLG c.153_158dup6 variant is predicted to result in an in-frame duplication (p.Pro52_Pro53dup). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.033% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too common to be causative of disease (http://gnomad.broadinstitute.org/variant/1-172628482-A-ACCACCG). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Autoimmune lymphoproliferative syndrome type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 02, 2022

This variant, c.153_158dup, results in the insertion of 2 amino acid(s) of the FASLG protein (p.Pro52_Pro53dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs749237778, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with FASLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 532228). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs749237778; hg19: chr1-172628482;