rs9658776

Variant names:

• chr10-89015215-T-C
• rs9658776
• ENST00000313771.10:n.2082T>C

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.2082T>C 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 0.0521 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 ENST00000313771.10 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.307
• Publications: 5 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=-0.9).
• BP6: Variant 10-89015215-T-C is Benign according to our data. Variant chr10-89015215-T-C is described in ClinVar as Benign. ClinVar VariationId is 301541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000313771.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	NM_000043.6	MANE Select	c.*765T>C		3_prime_UTR	Exon 9 of 9	NP_000034.1
	FAS	NR_028033.4		n.1680T>C		non_coding_transcript_exon	Exon 7 of 7
	FAS	NR_028034.4		n.1542T>C		non_coding_transcript_exon	Exon 6 of 6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	ENST00000313771.10	TSL:1	n.2082T>C		non_coding_transcript_exon	Exon 9 of 9
	FAS	ENST00000492756.7	TSL:1	n.*1202T>C		non_coding_transcript_exon	Exon 7 of 7	ENSP00000422453.1
	FAS	ENST00000652046.1	MANE Select	c.*765T>C		3_prime_UTR	Exon 9 of 9	ENSP00000498466.1

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

GnomAD2 exomes AF: 0.0724 AC: 9440 AN: 130450 AF XY: 0.0660

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 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

African (AFR) AF: 0.0119 AC: 148 AN: 12442

American (AMR) AF: 0.201 AC: 5971 AN: 29770

Ashkenazi Jewish (ASJ) AF: 0.0241 AC: 384 AN: 15906

East Asian (EAS) AF: 0.0225 AC: 462 AN: 20566

South Asian (SAS) AF: 0.0627 AC: 3783 AN: 60348

European-Finnish (FIN) AF: 0.0391 AC: 486 AN: 12422

Middle Eastern (MID) AF: 0.0439 AC: 72 AN: 1640

European-Non Finnish (NFE) AF: 0.0453 AC: 9464 AN: 208704

Other (OTH) AF: 0.0445 AC: 926 AN: 20800

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

African (AFR) AF: 0.0102 AC: 425 AN: 41566

American (AMR) AF: 0.116 AC: 1770 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3472

East Asian (EAS) AF: 0.0193 AC: 100 AN: 5188

South Asian (SAS) AF: 0.0556 AC: 268 AN: 4818

European-Finnish (FIN) AF: 0.0379 AC: 402 AN: 10606

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0442 AC: 3004 AN: 68006

Other (OTH) AF: 0.0440 AC: 93 AN: 2114

Alfa AF: 0.0450 Hom.: 239

Bravo AF: 0.0481

Asia WGS AF: 0.0390 AC: 135 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 13, 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.4
DANN	Benign	0.69
PhyloP100		0.31
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: rs9658776; hg19: chr10-90774972;