chr1-172664397-A-G

Position:

chr1-172664397-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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:2B:2

Conservation

PhyloP100: -0.128

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 links:

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ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.451+7A>G		splice_region_variant, intron_variant		ENST00000367721.3	NP_000630.1
FASLG	NM_001302746.2 linkuse as main transcript	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 linkuse as main transcript	c.451+7A>G		splice_region_variant, intron_variant		1	NM_000639.3	ENSP00000356694	P1	P48023-1
FASLG	ENST00000340030.4 linkuse as main transcript	c.*21+7A>G		splice_region_variant, intron_variant		1		ENSP00000344739		P48023-2

Frequencies

GnomAD3 genomes

AF:

0.00201

AC:

306

AN:

152222

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000442

AC XY:

AN XY:

135880

show subpopulations

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.:

Cov.:

AF XY:

0.000217

AC XY:

158

AN XY:

727124

show subpopulations

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.:

Cov.:

AF XY:

0.00173

AC XY:

129

AN XY:

74512

show subpopulations

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.:

Bravo

AF:

0.00228

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 1

Uncertain:1Benign: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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over