rs6586166

Variant names:

• chr10-88996308-C-T
• rs6586166
• NM_000043.6:c.30+5402C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000043.6(FAS):​c.30+5402C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 151,634 control chromosomes in the GnomAD database, including 26,282 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.57 (26282 hom., cov: 30)
• Consequence: FAS NM_000043.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.442
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAS	NM_000043.6	c.30+5402C>T		intron_variant	Intron 1 of 8	ENST00000652046.1	NP_000034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046.1	c.30+5402C>T		intron_variant	Intron 1 of 8		NM_000043.6	ENSP00000498466.1

Frequencies

GnomAD3 genomes AF: 0.573 AC: 86836 AN: 151512 Hom.: 26225 Cov.: 30

Gnomad AFR AF: 0.779

Gnomad AMI AF: 0.482

Gnomad AMR AF: 0.551

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.451

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.496

Gnomad OTH AF: 0.548

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

GnomAD4 genome AF: 0.573 AC: 86960 AN: 151634 Hom.: 26282 Cov.: 30 AF XY: 0.570 AC XY: 42197 AN XY: 74056

African (AFR) AF: 0.779 AC: 32146 AN: 41278

American (AMR) AF: 0.552 AC: 8412 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1500 AN: 3466

East Asian (EAS) AF: 0.472 AC: 2435 AN: 5162

South Asian (SAS) AF: 0.450 AC: 2165 AN: 4808

European-Finnish (FIN) AF: 0.466 AC: 4884 AN: 10474

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.496 AC: 33670 AN: 67888

Other (OTH) AF: 0.552 AC: 1161 AN: 2104

Alfa AF: 0.537 Hom.: 2839

Bravo AF: 0.590

Asia WGS AF: 0.542 AC: 1885 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	13
DANN	Benign	0.85
PhyloP100		0.44
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: rs6586166; hg19: chr10-90756065;