rs9658786

Positions:

• chr10-89016592-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000043.6(FAS):​c.*2142C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 224,486 control chromosomes in the GnomAD database, including 1,850 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 0.11 (1206 hom., cov: 32)
  • Exomes 𝑓: 0.12 (644 hom.)
• Consequence: FAS NM_000043.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.504

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAS	NM_000043.6	c.*2142C>T		3_prime_UTR_variant	9/9	ENST00000652046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAS	ENST00000652046.1	c.*2142C>T		3_prime_UTR_variant	9/9		NM_000043.6	A2

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16880 AN: 152026 Hom.: 1209 Cov.: 32

Gnomad AFR AF: 0.0293

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.00809

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.112

GnomAD4 exome AF: 0.119 AC: 8626 AN: 72342 Hom.: 644 Cov.: 0 AF XY: 0.122 AC XY: 4068 AN XY: 33420

Gnomad4 AFR exome AF: 0.0302

Gnomad4 AMR exome AF: 0.0951

Gnomad4 ASJ exome AF: 0.129

Gnomad4 EAS exome AF: 0.00567

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.150

Gnomad4 NFE exome AF: 0.152

Gnomad4 OTH exome AF: 0.128

GnomAD4 genome AF: 0.111 AC: 16873 AN: 152144 Hom.: 1206 Cov.: 32 AF XY: 0.109 AC XY: 8106 AN XY: 74384

Gnomad4 AFR AF: 0.0293

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.138

Gnomad4 EAS AF: 0.00830

Gnomad4 SAS AF: 0.105

Gnomad4 FIN AF: 0.176

Gnomad4 NFE AF: 0.159

Gnomad4 OTH AF: 0.111

Alfa AF: 0.143 Hom.: 1601

Bravo AF: 0.101

Asia WGS AF: 0.0500 AC: 173 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.1
DANN	Benign	0.81

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs9658786; hg19: chr10-90776349;