rs9658786

Variant names:

• chr10-89016592-C-T
• rs9658786
• ENST00000492756.7:n.*2579C>T

Variant summary

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

The ENST00000492756.7(FAS):​n.*2579C>T variant causes a non coding transcript exon 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 ENST00000492756.7 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.504
• Publications: 9 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=-0.8).
• 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 rank	MANE	Protein	UniProt
FAS	NM_000043.6	c.*2142C>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000652046.1	NP_000034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046.1	c.*2142C>T		3_prime_UTR_variant	Exon 9 of 9		NM_000043.6	ENSP00000498466.1

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

African (AFR) AF: 0.0302 AC: 102 AN: 3382

American (AMR) AF: 0.0951 AC: 206 AN: 2166

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 592 AN: 4576

East Asian (EAS) AF: 0.00567 AC: 59 AN: 10406

South Asian (SAS) AF: 0.121 AC: 78 AN: 644

European-Finnish (FIN) AF: 0.150 AC: 9 AN: 60

Middle Eastern (MID) AF: 0.110 AC: 50 AN: 456

European-Non Finnish (NFE) AF: 0.152 AC: 6747 AN: 44520

Other (OTH) AF: 0.128 AC: 783 AN: 6132

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

African (AFR) AF: 0.0293 AC: 1219 AN: 41540

American (AMR) AF: 0.104 AC: 1586 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 478 AN: 3472

East Asian (EAS) AF: 0.00830 AC: 43 AN: 5178

South Asian (SAS) AF: 0.105 AC: 506 AN: 4818

European-Finnish (FIN) AF: 0.176 AC: 1857 AN: 10548

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10796 AN: 67984

Other (OTH) AF: 0.111 AC: 235 AN: 2112

Alfa AF: 0.137 Hom.: 2249

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
PhyloP100		-0.50

Splicing

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

Other links and lift over

dbSNP: rs9658786; hg19: chr10-90776349;