NM_000043.6:c.31-3173A>G

Variant names:

• chr10-88999856-A-G
• rs2147420
• NM_000043.6:c.31-3173A>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.31-3173A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 152,072 control chromosomes in the GnomAD database, including 19,653 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 0.50 (19653 hom., cov: 32)
• Consequence: FAS NM_000043.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.107
• Publications: 30 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAS	NM_000043.6	c.31-3173A>G		intron_variant	Intron 1 of 8	ENST00000652046.1	NP_000034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046.1	c.31-3173A>G		intron_variant	Intron 1 of 8		NM_000043.6	ENSP00000498466.1

Frequencies

GnomAD3 genomes AF: 0.500 AC: 75919 AN: 151956 Hom.: 19663 Cov.: 32

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.559

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.608

Gnomad EAS AF: 0.512

Gnomad SAS AF: 0.561

Gnomad FIN AF: 0.592

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.562

Gnomad OTH AF: 0.520

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

GnomAD4 genome AF: 0.499 AC: 75917 AN: 152072 Hom.: 19653 Cov.: 32 AF XY: 0.502 AC XY: 37298 AN XY: 74332

African (AFR) AF: 0.354 AC: 14694 AN: 41488

American (AMR) AF: 0.493 AC: 7535 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 2107 AN: 3468

East Asian (EAS) AF: 0.512 AC: 2656 AN: 5190

South Asian (SAS) AF: 0.561 AC: 2702 AN: 4818

European-Finnish (FIN) AF: 0.592 AC: 6244 AN: 10544

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.562 AC: 38219 AN: 67964

Other (OTH) AF: 0.515 AC: 1087 AN: 2110

Alfa AF: 0.474 Hom.: 5217

Bravo AF: 0.486

Asia WGS AF: 0.466 AC: 1621 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.5
DANN	Benign	0.80
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2147420; hg19: chr10-90759613;