10-89010241-T-C

Variant names:

• chr10-89010241-T-C
• rs982764
• NM_000043.6:c.444-298T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000043.6(FAS):​c.444-298T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 152,024 control chromosomes in the GnomAD database, including 8,126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.32 (8126 hom., cov: 32)
• Consequence: FAS NM_000043.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.594
• Publications: 28 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 10-89010241-T-C is Benign according to our data. Variant chr10-89010241-T-C is described in ClinVar as Benign. ClinVar VariationId is 1290654.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAS	NM_000043.6	c.444-298T>C		intron_variant	Intron 4 of 8	ENST00000652046.1	NP_000034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046.1	c.444-298T>C		intron_variant	Intron 4 of 8		NM_000043.6	ENSP00000498466.1

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48556 AN: 151906 Hom.: 8103 Cov.: 32

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.324

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.320 AC: 48623 AN: 152024 Hom.: 8126 Cov.: 32 AF XY: 0.324 AC XY: 24070 AN XY: 74310

African (AFR) AF: 0.272 AC: 11303 AN: 41480

American (AMR) AF: 0.414 AC: 6319 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 919 AN: 3466

East Asian (EAS) AF: 0.471 AC: 2438 AN: 5176

South Asian (SAS) AF: 0.360 AC: 1738 AN: 4822

European-Finnish (FIN) AF: 0.383 AC: 4036 AN: 10534

Middle Eastern (MID) AF: 0.291 AC: 85 AN: 292

European-Non Finnish (NFE) AF: 0.308 AC: 20911 AN: 67966

Other (OTH) AF: 0.322 AC: 681 AN: 2112

Alfa AF: 0.313 Hom.: 6747

Bravo AF: 0.317

Asia WGS AF: 0.439 AC: 1525 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.5
DANN	Benign	0.54
PhyloP100		-0.59
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: rs982764; hg19: chr10-90769998;