10-89012072-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000043.6(FAS):c.642T>C(p.Thr214=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.727 in 1,611,060 control chromosomes in the GnomAD database, including 428,901 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T214T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.73 (40584 hom., cov: 33)
  • Exomes 𝑓: 0.73 (388317 hom.)
• Consequence: FAS NM_000043.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.710

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 10-89012072-T-C is Benign according to our data. Variant chr10-89012072-T-C is described in ClinVar as [Benign]. Clinvar id is 254734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-89012072-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.951 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAS	NM_000043.6	c.642T>C	p.Thr214=	synonymous_variant	7/9	ENST00000652046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAS	ENST00000652046.1	c.642T>C	p.Thr214=	synonymous_variant	7/9		NM_000043.6	A2

Frequencies

GnomAD3 genomes AF: 0.727 AC: 110589 AN: 152056 Hom.: 40556 Cov.: 33

Gnomad AFR AF: 0.681

Gnomad AMI AF: 0.636

Gnomad AMR AF: 0.798

Gnomad ASJ AF: 0.748

Gnomad EAS AF: 0.973

Gnomad SAS AF: 0.819

Gnomad FIN AF: 0.794

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.704

Gnomad OTH AF: 0.746

GnomAD3 exomes AF: 0.766 AC: 192259 AN: 251130 Hom.: 74622 AF XY: 0.763 AC XY: 103622 AN XY: 135744

Gnomad AFR exome AF: 0.676

Gnomad AMR exome AF: 0.857

Gnomad ASJ exome AF: 0.733

Gnomad EAS exome AF: 0.983

Gnomad SAS exome AF: 0.824

Gnomad FIN exome AF: 0.789

Gnomad NFE exome AF: 0.699

Gnomad OTH exome AF: 0.748

GnomAD4 exome AF: 0.727 AC: 1060736 AN: 1458886 Hom.: 388317 Cov.: 35 AF XY: 0.729 AC XY: 529531 AN XY: 725916

Gnomad4 AFR exome AF: 0.677

Gnomad4 AMR exome AF: 0.847

Gnomad4 ASJ exome AF: 0.737

Gnomad4 EAS exome AF: 0.962

Gnomad4 SAS exome AF: 0.820

Gnomad4 FIN exome AF: 0.787

Gnomad4 NFE exome AF: 0.704

Gnomad4 OTH exome AF: 0.739

GnomAD4 genome AF: 0.727 AC: 110674 AN: 152174 Hom.: 40584 Cov.: 33 AF XY: 0.735 AC XY: 54652 AN XY: 74400

Gnomad4 AFR AF: 0.681

Gnomad4 AMR AF: 0.799

Gnomad4 ASJ AF: 0.748

Gnomad4 EAS AF: 0.974

Gnomad4 SAS AF: 0.819

Gnomad4 FIN AF: 0.794

Gnomad4 NFE AF: 0.704

Gnomad4 OTH AF: 0.742

Alfa AF: 0.714 Hom.: 102091

Bravo AF: 0.724

Asia WGS AF: 0.864 AC: 3005 AN: 3478

EpiCase AF: 0.695

EpiControl AF: 0.699

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 93% of patients studied by a panel of primary immunodeficiencies. Number of patients: 89. Only high quality variants are reported. -

Autoimmune lymphoproliferative syndrome type 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 15350189) -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	1.1
Dann	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2234978; hg19: chr10-90771829;