rs61756244

Variant names:

• chr1-172659348-G-A
• rs61756244
• NM_000639.3:c.147G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000639.3(FASLG):​c.147G>A​(p.Pro49Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00889 in 1,610,046 control chromosomes in the GnomAD database, including 1,023 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (567 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (456 hom.)
• Consequence: FASLG NM_000639.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.33
• Publications: 4 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: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• autoimmune lymphoproliferative syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 1-172659348-G-A is Benign according to our data. Variant chr1-172659348-G-A is described in ClinVar as Benign. ClinVar VariationId is 293729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.16 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASLG	NM_000639.3	MANE Select	c.147G>A	p.Pro49Pro	synonymous	Exon 1 of 4	NP_000630.1	P48023-1
	FASLG	NM_001302746.2		c.147G>A	p.Pro49Pro	synonymous	Exon 1 of 3	NP_001289675.1	P48023-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASLG	ENST00000367721.3	TSL:1 MANE Select	c.147G>A	p.Pro49Pro	synonymous	Exon 1 of 4	ENSP00000356694.2	P48023-1
	FASLG	ENST00000340030.4	TSL:1	c.147G>A	p.Pro49Pro	synonymous	Exon 1 of 3	ENSP00000344739.3	P48023-2
	FASLG	ENST00000875216.1		c.147G>A	p.Pro49Pro	synonymous	Exon 1 of 4	ENSP00000545275.1

Frequencies

GnomAD3 genomes AF: 0.0467 AC: 7091 AN: 151792 Hom.: 568 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0161

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0269

GnomAD2 exomes AF: 0.0121 AC: 2942 AN: 242834 AF XY: 0.00906

Gnomad AFR exome AF: 0.170

Gnomad AMR exome AF: 0.00578

Gnomad ASJ exome AF: 0.00497

Gnomad EAS exome AF: 0.000388

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000615

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00495 AC: 7218 AN: 1458138 Hom.: 456 Cov.: 32 AF XY: 0.00424 AC XY: 3073 AN XY: 725122

African (AFR) AF: 0.169 AC: 5636 AN: 33410

American (AMR) AF: 0.00663 AC: 294 AN: 44368

Ashkenazi Jewish (ASJ) AF: 0.00533 AC: 139 AN: 26056

East Asian (EAS) AF: 0.000656 AC: 26 AN: 39632

South Asian (SAS) AF: 0.000337 AC: 29 AN: 85968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52542

Middle Eastern (MID) AF: 0.00789 AC: 45 AN: 5702

European-Non Finnish (NFE) AF: 0.000350 AC: 389 AN: 1110312

Other (OTH) AF: 0.0110 AC: 660 AN: 60148

GnomAD4 genome AF: 0.0467 AC: 7097 AN: 151908 Hom.: 567 Cov.: 32 AF XY: 0.0454 AC XY: 3375 AN XY: 74276

African (AFR) AF: 0.163 AC: 6735 AN: 41344

American (AMR) AF: 0.0161 AC: 245 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00289 AC: 10 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000624 AC: 3 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 67960

Other (OTH) AF: 0.0267 AC: 56 AN: 2100

Alfa AF: 0.0252 Hom.: 118

Bravo AF: 0.0531

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Autoimmune lymphoproliferative syndrome type 1 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.19
DANN	Benign	0.57
PhyloP100		-1.3
PromoterAI		-0.0026	Neutral
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: rs61756244; hg19: chr1-172628488; COSMIC: COSV60680997;