rs9658776

chr10-89015215-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000043.6(FAS):c.*765T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0521 in 534,864 control chromosomes in the GnomAD database, including 1,316 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.040 (213 hom., cov: 32)
  • Exomes 𝑓: 0.057 (1103 hom.)
• Consequence: FAS NM_000043.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.307

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 10-89015215-T-C is Benign according to our data. Variant chr10-89015215-T-C is described in ClinVar as [Benign]. Clinvar id is 301541.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAS	NM_000043.6	c.*765T>C		3_prime_UTR_variant	9/9	ENST00000652046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAS	ENST00000652046.1	c.*765T>C		3_prime_UTR_variant	9/9		NM_000043.6	A2

Frequencies

GnomAD3 genomes AF: 0.0404 AC: 6143 AN: 152148 Hom.: 205 Cov.: 32

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.0194

Gnomad SAS AF: 0.0556

Gnomad FIN AF: 0.0379

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0442

Gnomad OTH AF: 0.0445

GnomAD3 exomes AF: 0.0724 AC: 9440 AN: 130450 Hom.: 706 AF XY: 0.0660 AC XY: 4700 AN XY: 71212

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.206

Gnomad ASJ exome AF: 0.0249

Gnomad EAS exome AF: 0.0145

Gnomad SAS exome AF: 0.0626

Gnomad FIN exome AF: 0.0407

Gnomad NFE exome AF: 0.0434

Gnomad OTH exome AF: 0.0577

GnomAD4 exome AF: 0.0567 AC: 21696 AN: 382598 Hom.: 1103 Cov.: 0 AF XY: 0.0554 AC XY: 11583 AN XY: 209126

Gnomad4 AFR exome AF: 0.0119

Gnomad4 AMR exome AF: 0.201

Gnomad4 ASJ exome AF: 0.0241

Gnomad4 EAS exome AF: 0.0225

Gnomad4 SAS exome AF: 0.0627

Gnomad4 FIN exome AF: 0.0391

Gnomad4 NFE exome AF: 0.0453

Gnomad4 OTH exome AF: 0.0445

GnomAD4 genome AF: 0.0405 AC: 6161 AN: 152266 Hom.: 213 Cov.: 32 AF XY: 0.0418 AC XY: 3112 AN XY: 74444

Gnomad4 AFR AF: 0.0102

Gnomad4 AMR AF: 0.116

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.0193

Gnomad4 SAS AF: 0.0556

Gnomad4 FIN AF: 0.0379

Gnomad4 NFE AF: 0.0442

Gnomad4 OTH AF: 0.0440

Alfa AF: 0.0425 Hom.: 37

Bravo AF: 0.0481

Asia WGS AF: 0.0390 AC: 135 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.90
Cadd	Benign	4.4
Dann	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs9658776; hg19: chr10-90774972;