rs4406737

Variant names:

• chr10-88999967-A-G
• rs4406737
• NM_000043.6:c.31-3062A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-88999967-A-G
• chr10-88999967-A-T

Variant summary

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

The NM_000043.6(FAS):​c.31-3062A>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 152,092 control chromosomes in the GnomAD database, including 19,648 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 (19648 hom., cov: 33)
• Consequence: FAS NM_000043.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.46
• Publications: 44 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=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.558 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.31-3062A>G		intron	N/A	NP_000034.1	P25445-1
	FAS	NM_001410956.1		c.76-3062A>G		intron	N/A	NP_001397885.1	A0A8Q3SIR6
	FAS	NM_152871.4		c.31-3062A>G		intron	N/A	NP_690610.1	P25445-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	ENST00000652046.1	MANE Select	c.31-3062A>G		intron	N/A	ENSP00000498466.1	P25445-1
	FAS	ENST00000357339.7	TSL:1	c.31-3062A>G		intron	N/A	ENSP00000349896.2	P25445-6
	FAS	ENST00000355279.2	TSL:1	c.31-3062A>G		intron	N/A	ENSP00000347426.2	P25445-7

Frequencies

GnomAD3 genomes AF: 0.499 AC: 75901 AN: 151976 Hom.: 19658 Cov.: 33

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.558

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.608

Gnomad EAS AF: 0.511

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: 75900 AN: 152092 Hom.: 19648 Cov.: 33 AF XY: 0.501 AC XY: 37267 AN XY: 74328

African (AFR) AF: 0.354 AC: 14679 AN: 41494

American (AMR) AF: 0.493 AC: 7539 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 2108 AN: 3468

East Asian (EAS) AF: 0.511 AC: 2647 AN: 5178

South Asian (SAS) AF: 0.561 AC: 2708 AN: 4824

European-Finnish (FIN) AF: 0.592 AC: 6235 AN: 10536

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

European-Non Finnish (NFE) AF: 0.562 AC: 38225 AN: 67986

Other (OTH) AF: 0.515 AC: 1088 AN: 2112

Alfa AF: 0.542 Hom.: 97962

Bravo AF: 0.486

Asia WGS AF: 0.468 AC: 1625 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.013
DANN	Benign	0.46
PhyloP100		-3.5
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: rs4406737; hg19: chr10-90759724;