rs1571019

Variant names:

• chr10-89013546-A-G
• rs1571019
• NM_000043.6:c.676+179A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000043.6(FAS):​c.676+179A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 152,028 control chromosomes in the GnomAD database, including 15,225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.45 (15225 hom., cov: 32)
• Consequence: FAS NM_000043.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0840
• Publications: 7 publications found

Genes affected

FAS (HGNC:11920): (Fas cell surface death receptor) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor contains a death domain. It has been shown to play a central role in the physiological regulation of programmed cell death, and has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The interaction of this receptor with its ligand allows the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10. The autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, and leads to apoptosis. This receptor has been also shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is found to be involved in transducing the proliferating signals in normal diploid fibroblast and T cells. Several alternatively spliced transcript variants have been described, some of which are candidates for nonsense-mediated mRNA decay (NMD). The isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform. [provided by RefSeq, Mar 2011]

FAS Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• autoimmune lymphoproliferative syndrome type 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 10-89013546-A-G is Benign according to our data. Variant chr10-89013546-A-G is described in ClinVar as Benign. ClinVar VariationId is 1250840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000043.6. 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
	FAS	NM_000043.6	MANE Select	c.676+179A>G		intron	N/A	NP_000034.1
	FAS	NM_001410956.1		c.721+179A>G		intron	N/A	NP_001397885.1
	FAS	NM_152871.4		c.613+179A>G		intron	N/A	NP_690610.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	ENST00000652046.1	MANE Select	c.676+179A>G		intron	N/A	ENSP00000498466.1
	FAS	ENST00000357339.7	TSL:1	c.613+179A>G		intron	N/A	ENSP00000349896.2
	FAS	ENST00000355279.2	TSL:1	c.652-573A>G		intron	N/A	ENSP00000347426.2

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67946 AN: 151910 Hom.: 15215 Cov.: 32

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.438

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.521

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.455

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.467

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.447 AC: 67982 AN: 152028 Hom.: 15225 Cov.: 32 AF XY: 0.452 AC XY: 33562 AN XY: 74308

African (AFR) AF: 0.417 AC: 17318 AN: 41496

American (AMR) AF: 0.500 AC: 7650 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 1753 AN: 3468

East Asian (EAS) AF: 0.521 AC: 2699 AN: 5178

South Asian (SAS) AF: 0.514 AC: 2477 AN: 4822

European-Finnish (FIN) AF: 0.447 AC: 4724 AN: 10564

Middle Eastern (MID) AF: 0.459 AC: 134 AN: 292

European-Non Finnish (NFE) AF: 0.440 AC: 29851 AN: 67902

Other (OTH) AF: 0.464 AC: 977 AN: 2106

Alfa AF: 0.450 Hom.: 5886

Bravo AF: 0.455

Asia WGS AF: 0.463 AC: 1600 AN: 3458

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.5
DANN	Benign	0.59
PhyloP100		-0.084
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1571019; hg19: chr10-90773303;