rs201525996

Positions:

• chr1-172664397-A-G
• chr1-172664397-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000639.3(FASLG):​c.451+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000416 in 1,614,008 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (3 hom.)
• Consequence: FASLG NM_000639.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001014
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -0.128

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-172664397-A-G is Benign according to our data. Variant chr1-172664397-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 293738.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=2}. Variant chr1-172664397-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 307 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FASLG	NM_000639.3	c.451+7A>G		splice_region_variant, intron_variant		ENST00000367721.3	NP_000630.1
FASLG	NM_001302746.2	c.*21+7A>G		splice_region_variant, intron_variant			NP_001289675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FASLG	ENST00000367721.3	c.451+7A>G		splice_region_variant, intron_variant		1	NM_000639.3	ENSP00000356694	P1
FASLG	ENST00000340030.4	c.*21+7A>G		splice_region_variant, intron_variant		1		ENSP00000344739

Frequencies

GnomAD3 genomes AF: 0.00201 AC: 306 AN: 152222 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00709

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000656 AC: 165 AN: 251410 Hom.: 1 AF XY: 0.000442 AC XY: 60 AN XY: 135880

Gnomad AFR exome AF: 0.00874

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000250 AC: 365 AN: 1461668 Hom.: 3 Cov.: 31 AF XY: 0.000217 AC XY: 158 AN XY: 727124

Gnomad4 AFR exome AF: 0.00917

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.00202 AC: 307 AN: 152340 Hom.: 2 Cov.: 32 AF XY: 0.00173 AC XY: 129 AN XY: 74512

Gnomad4 AFR AF: 0.00709

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.00228

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 1 Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Dec 20, 2017	FASLG NM_000639.2 exon 3 c.451+7A>G: This variant has not been reported in the literature but is present in 0.8% (206/24030) of African alleles including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs201525996). This variant is present in ClinVar (Variation ID:293738). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 04, 2024	- -

Lung cancer;C1328840:Autoimmune lymphoproliferative syndrome type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

FASLG NM_000639.2 exon 3 c.451+7A>G: This variant has been previously identified by our laboratory in 1 individual with vanishing bile duct syndrome and peripheral eosinophillia. This variant has not been reported in the literature but is present in 0.8% (207/24964) of African alleles including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs201525996). This variant is present in ClinVar (Variation ID:293738). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.23		Position offset: 14

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

Publications

LitVar

Other links and lift over

dbSNP: rs201525996; hg19: chr1-172633537;