10-89015015-A-C

Variant names:

• chr10-89015015-A-C
• rs1051070
• ENST00000313771.10:n.1882A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000313771.10(FAS):​n.1882A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000263 in 380,456 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: FAS ENST00000313771.10 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAS	NM_000043.6	c.*565A>C		3_prime_UTR_variant	Exon 9 of 9	ENST00000652046.1	NP_000034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046.1	c.*565A>C		3_prime_UTR_variant	Exon 9 of 9		NM_000043.6	ENSP00000498466.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000263 AC: 1 AN: 380456 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 207848

African (AFR) AF: 0.00 AC: 0 AN: 12312

American (AMR) AF: 0.00 AC: 0 AN: 29630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15868

East Asian (EAS) AF: 0.00 AC: 0 AN: 20468

South Asian (SAS) AF: 0.00 AC: 0 AN: 60186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1632

European-Non Finnish (NFE) AF: 0.00000482 AC: 1 AN: 207276

Other (OTH) AF: 0.00 AC: 0 AN: 20678

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.8
DANN	Benign	0.63
PhyloP100		1.2

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: rs1051070; hg19: chr10-90774772;