rs2862833

Positions:

• chr10-89015872-A-G

Variant summary

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

The NM_000043.6(FAS):​c.*1422A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 375,126 control chromosomes in the GnomAD database, including 39,554 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 0.45 (15243 hom., cov: 32)
  • Exomes 𝑓: 0.46 (24311 hom.)
• Consequence: FAS NM_000043.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.462

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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAS	NM_000043.6	c.*1422A>G		3_prime_UTR_variant	9/9	ENST00000652046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAS	ENST00000652046.1	c.*1422A>G		3_prime_UTR_variant	9/9		NM_000043.6	A2

Frequencies

GnomAD3 genomes AF: 0.448 AC: 67970 AN: 151858 Hom.: 15233 Cov.: 32

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.441

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.521

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.448

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.467

GnomAD4 exome AF: 0.462 AC: 103089 AN: 223150 Hom.: 24311 Cov.: 0 AF XY: 0.468 AC XY: 54778 AN XY: 117144

Gnomad4 AFR exome AF: 0.421

Gnomad4 AMR exome AF: 0.534

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.506

Gnomad4 SAS exome AF: 0.522

Gnomad4 FIN exome AF: 0.447

Gnomad4 NFE exome AF: 0.438

Gnomad4 OTH exome AF: 0.464

GnomAD4 genome AF: 0.447 AC: 68006 AN: 151976 Hom.: 15243 Cov.: 32 AF XY: 0.452 AC XY: 33577 AN XY: 74286

Gnomad4 AFR AF: 0.418

Gnomad4 AMR AF: 0.500

Gnomad4 ASJ AF: 0.505

Gnomad4 EAS AF: 0.521

Gnomad4 SAS AF: 0.514

Gnomad4 FIN AF: 0.448

Gnomad4 NFE AF: 0.440

Gnomad4 OTH AF: 0.464

Alfa AF: 0.450 Hom.: 7892

Bravo AF: 0.455

Asia WGS AF: 0.462 AC: 1605 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.0
DANN	Benign	0.73

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2862833; hg19: chr10-90775629;