rs7901656

Variant names:

• chr10-89006456-T-C
• rs7901656
• NM_000043.6:c.197-1244T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000043.6(FAS):​c.197-1244T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 152,130 control chromosomes in the GnomAD database, including 7,770 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (7770 hom., cov: 32)
• Consequence: FAS NM_000043.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.79
• Publications: 15 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000043.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	NM_000043.6	MANE Select	c.197-1244T>C		intron	N/A	NP_000034.1
	FAS	NM_001410956.1		c.242-1244T>C		intron	N/A	NP_001397885.1
	FAS	NM_152871.4		c.197-1244T>C		intron	N/A	NP_690610.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	ENST00000652046.1	MANE Select	c.197-1244T>C		intron	N/A	ENSP00000498466.1
	FAS	ENST00000357339.7	TSL:1	c.197-1244T>C		intron	N/A	ENSP00000349896.2
	FAS	ENST00000355279.2	TSL:1	c.197-1244T>C		intron	N/A	ENSP00000347426.2

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47335 AN: 152012 Hom.: 7770 Cov.: 32

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.502

Gnomad SAS AF: 0.425

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.342

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

GnomAD4 genome AF: 0.311 AC: 47341 AN: 152130 Hom.: 7770 Cov.: 32 AF XY: 0.314 AC XY: 23368 AN XY: 74360

African (AFR) AF: 0.212 AC: 8798 AN: 41514

American (AMR) AF: 0.329 AC: 5022 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1574 AN: 3470

East Asian (EAS) AF: 0.502 AC: 2603 AN: 5182

South Asian (SAS) AF: 0.427 AC: 2061 AN: 4826

European-Finnish (FIN) AF: 0.298 AC: 3146 AN: 10566

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.337 AC: 22918 AN: 67970

Other (OTH) AF: 0.340 AC: 718 AN: 2114

Alfa AF: 0.331 Hom.: 1787

Bravo AF: 0.310

Asia WGS AF: 0.396 AC: 1373 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.097
DANN	Benign	0.73
PhyloP100		-1.8
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: rs7901656; hg19: chr10-90766213;