chr1-172658997-C-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000639.3(FASLG):​c.-205C>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 923,756 control chromosomes in the GnomAD database, including 838 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (568 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (270 hom.)
• Consequence: FASLG NM_000639.3 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 1-172658997-C-G is Benign according to our data. Variant chr1-172658997-C-G is described in ClinVar as Benign. ClinVar VariationId is 1272607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 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.-205C>G		upstream_gene	N/A	NP_000630.1
	FASLG	NM_001302746.2		c.-205C>G		upstream_gene	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.-205C>G		upstream_gene	N/A	ENSP00000356694.2
	FASLG	ENST00000340030.4	TSL:1	c.-205C>G		upstream_gene	N/A	ENSP00000344739.3
	FASLG	ENST00000875216.1		c.-205C>G		upstream_gene	N/A	ENSP00000545275.1

Frequencies

GnomAD3 genomes AF: 0.0467 AC: 7109 AN: 152108 Hom.: 569 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0278

GnomAD4 exome AF: 0.00534 AC: 4118 AN: 771530 Hom.: 270 Cov.: 10 AF XY: 0.00456 AC XY: 1777 AN XY: 389576

African (AFR) AF: 0.167 AC: 3133 AN: 18770

American (AMR) AF: 0.00858 AC: 194 AN: 22604

Ashkenazi Jewish (ASJ) AF: 0.00531 AC: 87 AN: 16386

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

South Asian (SAS) AF: 0.000324 AC: 17 AN: 52490

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

Middle Eastern (MID) AF: 0.0114 AC: 30 AN: 2622

European-Non Finnish (NFE) AF: 0.000397 AC: 222 AN: 558982

Other (OTH) AF: 0.0118 AC: 435 AN: 36850

GnomAD4 genome AF: 0.0467 AC: 7116 AN: 152226 Hom.: 568 Cov.: 32 AF XY: 0.0453 AC XY: 3370 AN XY: 74426

African (AFR) AF: 0.163 AC: 6752 AN: 41498

American (AMR) AF: 0.0160 AC: 245 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 68018

Other (OTH) AF: 0.0275 AC: 58 AN: 2112

Alfa AF: 0.00836 Hom.: 11

Bravo AF: 0.0530

Asia WGS AF: 0.00953 AC: 33 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	18
DANN	Benign	0.72
PhyloP100		1.6
PromoterAI		0.022	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;