rs2296603

Variant names:

• chr10-89003370-C-T
• rs2296603
• NM_000043.6:c.196+176C>T

Variant summary

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

The NM_001410956.1(FAS):​c.241+176C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 151,992 control chromosomes in the GnomAD database, including 11,858 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.39 (11858 hom., cov: 33)
• Consequence: FAS NM_001410956.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.14
• Publications: 8 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=-0.9).
• BP6: Variant 10-89003370-C-T is Benign according to our data. Variant chr10-89003370-C-T is described in ClinVar as Benign. ClinVar VariationId is 1291169.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001410956.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	NM_000043.6	MANE Select	c.196+176C>T		intron	N/A	NP_000034.1
	FAS	NM_001410956.1		c.241+176C>T		intron	N/A	NP_001397885.1
	FAS	NM_152871.4		c.196+176C>T		intron	N/A	NP_690610.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	ENST00000652046.1	MANE Select	c.196+176C>T		intron	N/A	ENSP00000498466.1
	FAS	ENST00000357339.7	TSL:1	c.196+176C>T		intron	N/A	ENSP00000349896.2
	FAS	ENST00000355279.2	TSL:1	c.196+176C>T		intron	N/A	ENSP00000347426.2

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59548 AN: 151874 Hom.: 11860 Cov.: 33

Gnomad AFR AF: 0.329

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.469

Gnomad EAS AF: 0.499

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.410

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

GnomAD4 genome AF: 0.392 AC: 59554 AN: 151992 Hom.: 11858 Cov.: 33 AF XY: 0.396 AC XY: 29391 AN XY: 74280

African (AFR) AF: 0.328 AC: 13599 AN: 41450

American (AMR) AF: 0.390 AC: 5952 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 1627 AN: 3468

East Asian (EAS) AF: 0.499 AC: 2583 AN: 5176

South Asian (SAS) AF: 0.451 AC: 2169 AN: 4812

European-Finnish (FIN) AF: 0.421 AC: 4441 AN: 10542

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.409 AC: 27810 AN: 67954

Other (OTH) AF: 0.408 AC: 860 AN: 2110

Alfa AF: 0.400 Hom.: 1601

Bravo AF: 0.388

Asia WGS AF: 0.417 AC: 1450 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.016
DANN	Benign	0.48
PhyloP100		-3.1
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: rs2296603; hg19: chr10-90763127;