rs2296601

chr10-89007883-C-T

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.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:2
• Conservation: PhyloP100: 0.346

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=-0.8).
• BP6: Variant 10-89007883-C-T is Benign according to our data. Variant chr10-89007883-C-T is described in ClinVar as [Benign]. Clinvar id 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/exons	MANE	UniProt
FAS	NM_000043.6	c.334+46C>T		intron_variant		ENST00000652046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAS	ENST00000652046.1	c.334+46C>T		intron_variant			NM_000043.6	A2

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

GnomAD3 exomes AF: 0.165 AC: 41134 AN: 248930 Hom.: 4440 AF XY: 0.161 AC XY: 21715 AN XY: 134844

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 SAS exome AF: 0.182

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

Gnomad4 AFR exome AF: 0.225

Gnomad4 AMR exome AF: 0.191

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.448

Gnomad4 SAS exome AF: 0.179

Gnomad4 FIN exome AF: 0.160

Gnomad4 NFE exome AF: 0.103

Gnomad4 OTH exome AF: 0.147

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

Gnomad4 AFR AF: 0.231

Gnomad4 AMR AF: 0.194

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.442

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.169

Gnomad4 NFE AF: 0.105

Gnomad4 OTH AF: 0.165

Alfa AF: 0.128 Hom.: 264

Bravo AF: 0.168

Asia WGS AF: 0.346 AC: 1204 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

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 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 19. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	6.5
Dann	Benign	0.63

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: rs2296601; hg19: chr10-90767640; COSMIC: COSV58238899; COSMIC: COSV58238899;