NM_000639.3:c.395-124A>G

Variant names:

• chr1-172664210-A-G
• rs5030772
• NM_000639.3:c.395-124A>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.395-124A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 954,906 control chromosomes in the GnomAD database, including 8,417 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.099 (1080 hom., cov: 32)
  • Exomes 𝑓: 0.13 (7337 hom.)
• Consequence: FASLG NM_000639.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.181
• Publications: 51 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=-0.89).
• BP6: Variant 1-172664210-A-G is Benign according to our data. Variant chr1-172664210-A-G is described in ClinVar as Benign. ClinVar VariationId is 1273293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.146 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.395-124A>G		intron	N/A	NP_000630.1
	FASLG	NM_001302746.2		c.349-124A>G		intron	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.395-124A>G		intron	N/A	ENSP00000356694.2
	FASLG	ENST00000340030.4	TSL:1	c.349-124A>G		intron	N/A	ENSP00000344739.3

Frequencies

GnomAD3 genomes AF: 0.0991 AC: 15081 AN: 152130 Hom.: 1079 Cov.: 32

Gnomad AFR AF: 0.0252

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.0983

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0940

Gnomad FIN AF: 0.0841

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.117

GnomAD4 exome AF: 0.127 AC: 101683 AN: 802658 Hom.: 7337 AF XY: 0.127 AC XY: 53106 AN XY: 417166

African (AFR) AF: 0.0234 AC: 455 AN: 19464

American (AMR) AF: 0.0709 AC: 2362 AN: 33304

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 3780 AN: 20638

East Asian (EAS) AF: 0.000248 AC: 8 AN: 32298

South Asian (SAS) AF: 0.110 AC: 7170 AN: 65336

European-Finnish (FIN) AF: 0.0926 AC: 4341 AN: 46892

Middle Eastern (MID) AF: 0.139 AC: 393 AN: 2828

European-Non Finnish (NFE) AF: 0.144 AC: 78470 AN: 544302

Other (OTH) AF: 0.125 AC: 4704 AN: 37596

GnomAD4 genome AF: 0.0991 AC: 15081 AN: 152248 Hom.: 1080 Cov.: 32 AF XY: 0.0958 AC XY: 7132 AN XY: 74436

African (AFR) AF: 0.0251 AC: 1045 AN: 41572

American (AMR) AF: 0.0981 AC: 1501 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 649 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5190

South Asian (SAS) AF: 0.0943 AC: 455 AN: 4824

European-Finnish (FIN) AF: 0.0841 AC: 892 AN: 10602

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.149 AC: 10103 AN: 67982

Other (OTH) AF: 0.115 AC: 243 AN: 2110

Alfa AF: 0.117 Hom.: 141

Bravo AF: 0.0976

Asia WGS AF: 0.0420 AC: 146 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.9
DANN	Benign	0.43
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs5030772; hg19: chr1-172633350;