rs140406512

chr1-172660110-C-Achr1-172660110-C-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.364C>A(p.His122Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000526 in 1,614,104 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (1 hom.)
• Consequence: FASLG NM_000639.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.881

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 (MetaRNN=0.028116256).
• BP6: Variant 1-172660110-C-A is Benign according to our data. Variant chr1-172660110-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 293736.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
• BS2: High AC in GnomAd at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASLG	NM_000639.3	c.364C>A	p.His122Asn	missense_variant	2/4	ENST00000367721.3
FASLG	NM_001302746.2	c.348+561C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASLG	ENST00000367721.3	c.364C>A	p.His122Asn	missense_variant	2/4	1	NM_000639.3	P1
FASLG	ENST00000340030.4	c.348+561C>A		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000286 AC: 72 AN: 251348 Hom.: 0 AF XY: 0.000294 AC XY: 40 AN XY: 135840

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000590

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000547 AC: 799 AN: 1461786 Hom.: 1 Cov.: 30 AF XY: 0.000520 AC XY: 378 AN XY: 727194

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000683

Gnomad4 OTH exome AF: 0.000546

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74486

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000394 Hom.: 0

Bravo AF: 0.000321

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000280 AC: 34

EpiCase AF: 0.000327

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 31, 2022	This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 122 of the FASLG protein (p.His122Asn). This variant is present in population databases (rs140406512, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with FASLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 293736). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.364C>A (p.H122N) alteration is located in exon 2 (coding exon 2) of the FASLG gene. This alteration results from a C to A substitution at nucleotide position 364, causing the histidine (H) at amino acid position 122 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	8.3
Dann	Benign	0.58
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.11
Sift	Benign	0.66	T
Sift4G	Benign	0.38	T
Polyphen		0.0010	B
Vest4		0.17
MVP		0.30
MPC		0.14
ClinPred		0.019	T
GERP RS		3.8
Varity_R		0.042
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140406512; hg19: chr1-172629250; COSMIC: COSV99056908;