rs1051070

chr10-89015015-A-T

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.*565A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0755 in 532,728 control chromosomes in the GnomAD database, including 2,086 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.068 (521 hom., cov: 32)
  • Exomes 𝑓: 0.078 (1565 hom.)
• Consequence: FAS NM_000043.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.18

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=-0.86).
• BP6: Variant 10-89015015-A-T is Benign according to our data. Variant chr10-89015015-A-T is described in ClinVar as [Benign]. Clinvar id is 301537.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAS	NM_000043.6	c.*565A>T		3_prime_UTR_variant	9/9	ENST00000652046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAS	ENST00000652046.1	c.*565A>T		3_prime_UTR_variant	9/9		NM_000043.6	A2

Frequencies

GnomAD3 genomes AF: 0.0684 AC: 10405 AN: 152184 Hom.: 521 Cov.: 32

Gnomad AFR AF: 0.0192

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0582

Gnomad ASJ AF: 0.0876

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0167

Gnomad FIN AF: 0.0518

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.0646

GnomAD3 exomes AF: 0.0659 AC: 8570 AN: 130106 Hom.: 422 AF XY: 0.0647 AC XY: 4593 AN XY: 71032

Gnomad AFR exome AF: 0.0150

Gnomad AMR exome AF: 0.0492

Gnomad ASJ exome AF: 0.0954

Gnomad EAS exome AF: 0.000384

Gnomad SAS exome AF: 0.0166

Gnomad FIN exome AF: 0.0569

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.0710

GnomAD4 exome AF: 0.0784 AC: 29832 AN: 380426 Hom.: 1565 Cov.: 0 AF XY: 0.0733 AC XY: 15233 AN XY: 207830

Gnomad4 AFR exome AF: 0.0174

Gnomad4 AMR exome AF: 0.0493

Gnomad4 ASJ exome AF: 0.0941

Gnomad4 EAS exome AF: 0.0000977

Gnomad4 SAS exome AF: 0.0171

Gnomad4 FIN exome AF: 0.0651

Gnomad4 NFE exome AF: 0.111

Gnomad4 OTH exome AF: 0.0834

GnomAD4 genome AF: 0.0683 AC: 10403 AN: 152302 Hom.: 521 Cov.: 32 AF XY: 0.0647 AC XY: 4819 AN XY: 74474

Gnomad4 AFR AF: 0.0191

Gnomad4 AMR AF: 0.0580

Gnomad4 ASJ AF: 0.0876

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0166

Gnomad4 FIN AF: 0.0518

Gnomad4 NFE AF: 0.112

Gnomad4 OTH AF: 0.0639

Alfa AF: 0.0876 Hom.: 129

Bravo AF: 0.0678

Asia WGS AF: 0.0100 AC: 36 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 12, 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	-0.86
Cadd	Benign	4.7
Dann	Benign	0.48

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: rs1051070; hg19: chr10-90774772;