1-172658997-C-A

Variant names:

• chr1-172658997-C-A
• rs74124371
• NM_000639.3:c.-205C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000639.3(FASLG):​c.-205C>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000259 in 771,556 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: FASLG NM_000639.3 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.57
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FASLG	NM_000639.3	c.-205C>A		upstream_gene_variant		ENST00000367721.3	NP_000630.1
FASLG	NM_001302746.2	c.-205C>A		upstream_gene_variant			NP_001289675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FASLG	ENST00000367721.3	c.-205C>A		upstream_gene_variant		1	NM_000639.3	ENSP00000356694.2
FASLG	ENST00000340030.4	c.-205C>A		upstream_gene_variant		1		ENSP00000344739.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000259 AC: 2 AN: 771556 Hom.: 0 Cov.: 10 AF XY: 0.00000257 AC XY: 1 AN XY: 389588

African (AFR) AF: 0.0000532 AC: 1 AN: 18790

American (AMR) AF: 0.00 AC: 0 AN: 22606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16386

East Asian (EAS) AF: 0.00 AC: 0 AN: 32632

South Asian (SAS) AF: 0.00 AC: 0 AN: 52490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2622

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 558984

Other (OTH) AF: 0.0000271 AC: 1 AN: 36852

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 11

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Benign	0.73
PhyloP100		1.6
PromoterAI		0.030	Neutral

Splicing

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

Other links and lift over

dbSNP: rs74124371; hg19: chr1-172628137;