chr1-172659348-G-A

Position:

• chr1-172659348-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000639.3(FASLG):​c.147G>A​(p.Pro49=) 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

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 Benign. Variant got -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 id is 293729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-172659348-G-A is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FASLG	NM_000639.3	c.147G>A	p.Pro49=	synonymous_variant	1/4	ENST00000367721.3	NP_000630.1
FASLG	NM_001302746.2	c.147G>A	p.Pro49=	synonymous_variant	1/3		NP_001289675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FASLG	ENST00000367721.3	c.147G>A	p.Pro49=	synonymous_variant	1/4	1	NM_000639.3	ENSP00000356694	P1
FASLG	ENST00000340030.4	c.147G>A	p.Pro49=	synonymous_variant	1/3	1		ENSP00000344739

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

GnomAD3 exomes AF: 0.0121 AC: 2942 AN: 242834 Hom.: 211 AF XY: 0.00906 AC XY: 1193 AN XY: 131738

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 SAS exome AF: 0.000331

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

Gnomad4 AFR exome AF: 0.169

Gnomad4 AMR exome AF: 0.00663

Gnomad4 ASJ exome AF: 0.00533

Gnomad4 EAS exome AF: 0.000656

Gnomad4 SAS exome AF: 0.000337

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000350

Gnomad4 OTH exome AF: 0.0110

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

Gnomad4 AFR AF: 0.163

Gnomad4 AMR AF: 0.0161

Gnomad4 ASJ AF: 0.00289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.0267

Alfa AF: 0.0252 Hom.: 118

Bravo AF: 0.0531

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autoimmune lymphoproliferative syndrome type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.19
DANN	Benign	0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs61756244; hg19: chr1-172628488; COSMIC: COSV60680997;