Genetic Variant FASLG:c.-205C>G (chr1-172658997-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000639.3(FASLG):c.-205C>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 923,756 control chromosomes in the GnomAD database, including 838 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 568 hom., cov: 32)

Exomes 𝑓: 0.0053 ( 270 hom. )

Consequence

FASLG
NM_000639.3 upstream_gene

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.57

Publications

1 publications found

Variant links:

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

FASLG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 1-172658997-C-G is Benign according to our data. Variant chr1-172658997-C-G is described in ClinVar as Benign. ClinVar VariationId is 1272607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FASLG	NM_000639.3 link	c.-205C>G		upstream_gene_variant		ENST00000367721.3	NP_000630.1	P48023-1Q53ZZ1
FASLG	NM_001302746.2 link	c.-205C>G		upstream_gene_variant			NP_001289675.1	P48023-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FASLG	ENST00000367721.3 link	c.-205C>G		upstream_gene_variant		1	NM_000639.3	ENSP00000356694.2		P48023-1
FASLG	ENST00000340030.4 link	c.-205C>G		upstream_gene_variant		1		ENSP00000344739.3		P48023-2

Frequencies

GnomAD3 genomes

AF:

0.0467

AC:

7109

AN:

152108

Hom.:

569

Cov.:

show subpopulations

Gnomad AFR

AF:

0.163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0160

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.000559

Gnomad OTH

AF:

0.0278

GnomAD4 exome

AF:

0.00534

AC:

4118

AN:

771530

Hom.:

270

Cov.:

AF XY:

0.00456

AC XY:

1777

AN XY:

389576

show subpopulations

African (AFR)

AF:

0.167

AC:

3133

AN:

18770

American (AMR)

AF:

0.00858

AC:

194

AN:

22604

Ashkenazi Jewish (ASJ)

AF:

0.00531

AC:

AN:

16386

East Asian (EAS)

AF:

0.00

AC:

AN:

32632

South Asian (SAS)

AF:

0.000324

AC:

AN:

52490

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30194

Middle Eastern (MID)

AF:

0.0114

AC:

AN:

2622

European-Non Finnish (NFE)

AF:

0.000397

AC:

222

AN:

558982

Other (OTH)

AF:

0.0118

AC:

435

AN:

36850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

189

377

566

754

943

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

252

336

420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0467

AC:

7116

AN:

152226

Hom.:

568

Cov.:

AF XY:

0.0453

AC XY:

3370

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.163

AC:

6752

AN:

41498

American (AMR)

AF:

0.0160

AC:

245

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000559

AC:

AN:

68018

Other (OTH)

AF:

0.0275

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

316

632

947

1263

1579

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00836

Hom.:

Bravo

AF:

0.0530

Asia WGS

AF:

0.00953

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 29, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.72

PhyloP100

1.6

PromoterAI

0.022

Neutral

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over