rs2296603

Positions:

• chr10-89003370-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000043.6(FAS):​c.196+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_000043.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.14

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAS	NM_000043.6	c.196+176C>T		intron_variant		ENST00000652046.1	NP_000034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046.1	c.196+176C>T		intron_variant			NM_000043.6	ENSP00000498466	A2

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

Gnomad4 AFR AF: 0.328

Gnomad4 AMR AF: 0.390

Gnomad4 ASJ AF: 0.469

Gnomad4 EAS AF: 0.499

Gnomad4 SAS AF: 0.451

Gnomad4 FIN AF: 0.421

Gnomad4 NFE AF: 0.409

Gnomad4 OTH AF: 0.408

Alfa AF: 0.402 Hom.: 1556

Bravo AF: 0.388

Asia WGS AF: 0.417 AC: 1450 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.90
CADD	Benign	0.016
DANN	Benign	0.48

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: rs2296603; hg19: chr10-90763127;