rs2296601

Variant names:

• chr10-89007883-C-T
• rs2296601
• NM_000043.6:c.334+46C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000043.6(FAS):​c.334+46C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,611,144 control chromosomes in the GnomAD database, including 17,569 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2617 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14952 hom.)
• Consequence: FAS NM_000043.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.346
• Publications: 13 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=-0.8).
• BP6: Variant 10-89007883-C-T is Benign according to our data. Variant chr10-89007883-C-T is described in ClinVar as Benign. ClinVar VariationId is 1235502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAS	NM_000043.6	c.334+46C>T		intron_variant	Intron 3 of 8	ENST00000652046.1	NP_000034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046.1	c.334+46C>T		intron_variant	Intron 3 of 8		NM_000043.6	ENSP00000498466.1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25448 AN: 151918 Hom.: 2603 Cov.: 32

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.164

GnomAD2 exomes AF: 0.165 AC: 41134 AN: 248930 AF XY: 0.161

Gnomad AFR exome AF: 0.226

Gnomad AMR exome AF: 0.191

Gnomad ASJ exome AF: 0.0988

Gnomad EAS exome AF: 0.450

Gnomad FIN exome AF: 0.170

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.126 AC: 184478 AN: 1459108 Hom.: 14952 Cov.: 34 AF XY: 0.127 AC XY: 92369 AN XY: 725930

African (AFR) AF: 0.225 AC: 7502 AN: 33416

American (AMR) AF: 0.191 AC: 8548 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2691 AN: 26114

East Asian (EAS) AF: 0.448 AC: 17778 AN: 39678

South Asian (SAS) AF: 0.179 AC: 15465 AN: 86188

European-Finnish (FIN) AF: 0.160 AC: 8277 AN: 51800

Middle Eastern (MID) AF: 0.117 AC: 671 AN: 5756

European-Non Finnish (NFE) AF: 0.103 AC: 114710 AN: 1111180

Other (OTH) AF: 0.147 AC: 8836 AN: 60310

GnomAD4 genome AF: 0.168 AC: 25498 AN: 152036 Hom.: 2617 Cov.: 32 AF XY: 0.172 AC XY: 12802 AN XY: 74308

African (AFR) AF: 0.231 AC: 9557 AN: 41446

American (AMR) AF: 0.194 AC: 2967 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 363 AN: 3464

East Asian (EAS) AF: 0.442 AC: 2285 AN: 5166

South Asian (SAS) AF: 0.200 AC: 963 AN: 4818

European-Finnish (FIN) AF: 0.169 AC: 1785 AN: 10560

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7123 AN: 67986

Other (OTH) AF: 0.165 AC: 348 AN: 2114

Alfa AF: 0.130 Hom.: 281

Bravo AF: 0.168

Asia WGS AF: 0.346 AC: 1204 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 19. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.5
DANN	Benign	0.63
PhyloP100		0.35
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: rs2296601; hg19: chr10-90767640; COSMIC: COSV58238899; COSMIC: COSV58238899;