10-89016326-A-G

Variant names:

• chr10-89016326-A-G
• rs1800623
• NM_000043.6:c.*1876A>G

Variant summary

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

The NM_000043.6(FAS):​c.*1876A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.733 in 218,146 control chromosomes in the GnomAD database, including 59,312 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 0.73 (40532 hom., cov: 32)
  • Exomes 𝑓: 0.75 (18780 hom.)
• Consequence: FAS NM_000043.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24
• Publications: 7 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 type 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autoimmune lymphoproliferative syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.951 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	NM_000043.6	MANE Select	c.*1876A>G		3_prime_UTR	Exon 9 of 9	NP_000034.1	P25445-1
	FAS	NM_001410956.1		c.*1876A>G		3_prime_UTR	Exon 9 of 9	NP_001397885.1	A0A8Q3SIR6
	FAS	NM_152871.4		c.*1876A>G		3_prime_UTR	Exon 8 of 8	NP_690610.1	P25445-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	ENST00000652046.1	MANE Select	c.*1876A>G		3_prime_UTR	Exon 9 of 9	ENSP00000498466.1	P25445-1
	FAS	ENST00000357339.7	TSL:1	c.*1876A>G		3_prime_UTR	Exon 8 of 8	ENSP00000349896.2	P25445-6
	FAS	ENST00000492756.7	TSL:1	n.*2313A>G		non_coding_transcript_exon	Exon 7 of 7	ENSP00000422453.1	P25445-5

Frequencies

GnomAD3 genomes AF: 0.727 AC: 110488 AN: 151998 Hom.: 40504 Cov.: 32

Gnomad AFR AF: 0.680

Gnomad AMI AF: 0.638

Gnomad AMR AF: 0.797

Gnomad ASJ AF: 0.745

Gnomad EAS AF: 0.973

Gnomad SAS AF: 0.818

Gnomad FIN AF: 0.794

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.704

Gnomad OTH AF: 0.746

GnomAD4 exome AF: 0.748 AC: 49383 AN: 66030 Hom.: 18780 Cov.: 0 AF XY: 0.748 AC XY: 22868 AN XY: 30564

African (AFR) AF: 0.679 AC: 2080 AN: 3064

American (AMR) AF: 0.797 AC: 1586 AN: 1990

Ashkenazi Jewish (ASJ) AF: 0.742 AC: 3128 AN: 4216

East Asian (EAS) AF: 0.949 AC: 9183 AN: 9674

South Asian (SAS) AF: 0.814 AC: 464 AN: 570

European-Finnish (FIN) AF: 0.792 AC: 38 AN: 48

Middle Eastern (MID) AF: 0.740 AC: 305 AN: 412

European-Non Finnish (NFE) AF: 0.704 AC: 28521 AN: 40520

Other (OTH) AF: 0.737 AC: 4078 AN: 5536

GnomAD4 genome AF: 0.727 AC: 110573 AN: 152116 Hom.: 40532 Cov.: 32 AF XY: 0.734 AC XY: 54591 AN XY: 74358

African (AFR) AF: 0.680 AC: 28212 AN: 41474

American (AMR) AF: 0.798 AC: 12200 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.745 AC: 2586 AN: 3470

East Asian (EAS) AF: 0.974 AC: 5039 AN: 5176

South Asian (SAS) AF: 0.818 AC: 3948 AN: 4824

European-Finnish (FIN) AF: 0.794 AC: 8398 AN: 10582

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.704 AC: 47828 AN: 67978

Other (OTH) AF: 0.742 AC: 1568 AN: 2114

Alfa AF: 0.728 Hom.: 6790

Bravo AF: 0.723

Asia WGS AF: 0.864 AC: 3003 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.20
DANN	Benign	0.46
PhyloP100		-1.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1800623; hg19: chr10-90776083;