ENST00000313771.10:n.2401C>T

Variant names:

• chr10-89015534-C-T
• rs1468063
• ENST00000313771.10:n.2401C>T

Variant summary

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

The ENST00000313771.10(FAS):​n.2401C>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 0.155 in 533,818 control chromosomes in the GnomAD database, including 8,367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2668 hom., cov: 32)
  • Exomes 𝑓: 0.15 (5699 hom.)
• Consequence: FAS ENST00000313771.10 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.624
• Publications: 37 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=-0.92).
• BP6: Variant 10-89015534-C-T is Benign according to our data. Variant chr10-89015534-C-T is described in ClinVar as Benign. ClinVar VariationId is 301544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.429 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAS	NM_000043.6	c.*1084C>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.*1084C>T		3_prime_UTR_variant	Exon 9 of 9		NM_000043.6	ENSP00000498466.1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25580 AN: 151842 Hom.: 2654 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.0670

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.444

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.166

GnomAD2 exomes AF: 0.169 AC: 22034 AN: 130294 AF XY: 0.165

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.186

Gnomad ASJ exome AF: 0.0983

Gnomad EAS exome AF: 0.455

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.149 AC: 56862 AN: 381858 Hom.: 5699 Cov.: 0 AF XY: 0.148 AC XY: 30983 AN XY: 208690

African (AFR) AF: 0.231 AC: 2871 AN: 12428

American (AMR) AF: 0.186 AC: 5537 AN: 29746

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 1650 AN: 15894

East Asian (EAS) AF: 0.454 AC: 9291 AN: 20482

South Asian (SAS) AF: 0.177 AC: 10657 AN: 60100

European-Finnish (FIN) AF: 0.150 AC: 1861 AN: 12390

Middle Eastern (MID) AF: 0.122 AC: 200 AN: 1638

European-Non Finnish (NFE) AF: 0.104 AC: 21737 AN: 208422

Other (OTH) AF: 0.147 AC: 3058 AN: 20758

GnomAD4 genome AF: 0.169 AC: 25636 AN: 151960 Hom.: 2668 Cov.: 32 AF XY: 0.173 AC XY: 12867 AN XY: 74256

African (AFR) AF: 0.233 AC: 9668 AN: 41422

American (AMR) AF: 0.196 AC: 2985 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 363 AN: 3472

East Asian (EAS) AF: 0.444 AC: 2295 AN: 5170

South Asian (SAS) AF: 0.200 AC: 963 AN: 4822

European-Finnish (FIN) AF: 0.169 AC: 1783 AN: 10524

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7121 AN: 67964

Other (OTH) AF: 0.166 AC: 351 AN: 2114

Alfa AF: 0.130 Hom.: 4791

Bravo AF: 0.168

Asia WGS AF: 0.350 AC: 1216 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autoimmune lymphoproliferative syndrome type 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.41
DANN	Benign	0.46
PhyloP100		-0.62
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: rs1468063; hg19: chr10-90775291;