NM_000043.6:c.443+701T>C

Variant names:

• chr10-89009698-T-C
• rs9658757
• NM_000043.6:c.443+701T>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.443+701T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 152,186 control chromosomes in the GnomAD database, including 1,207 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 0.11 (1207 hom., cov: 32)
• Consequence: FAS NM_000043.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.612
• Publications: 1 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.156 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.443+701T>C		intron	N/A	NP_000034.1	P25445-1
	FAS	NM_001410956.1		c.488+701T>C		intron	N/A	NP_001397885.1	A0A8Q3SIR6
	FAS	NM_152871.4		c.443+701T>C		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.443+701T>C		intron	N/A	ENSP00000498466.1	P25445-1
	FAS	ENST00000357339.7	TSL:1	c.443+701T>C		intron	N/A	ENSP00000349896.2	P25445-6
	FAS	ENST00000355279.2	TSL:1	c.443+701T>C		intron	N/A	ENSP00000347426.2	P25445-7

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16848 AN: 152068 Hom.: 1210 Cov.: 32

Gnomad AFR AF: 0.0289

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.00768

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.113

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

GnomAD4 genome AF: 0.111 AC: 16841 AN: 152186 Hom.: 1207 Cov.: 32 AF XY: 0.109 AC XY: 8088 AN XY: 74408

African (AFR) AF: 0.0290 AC: 1205 AN: 41568

American (AMR) AF: 0.103 AC: 1574 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 478 AN: 3472

East Asian (EAS) AF: 0.00789 AC: 41 AN: 5194

South Asian (SAS) AF: 0.105 AC: 504 AN: 4818

European-Finnish (FIN) AF: 0.175 AC: 1856 AN: 10596

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10793 AN: 67986

Other (OTH) AF: 0.112 AC: 237 AN: 2114

Alfa AF: 0.132 Hom.: 212

Bravo AF: 0.100

Asia WGS AF: 0.0490 AC: 170 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.2
DANN	Benign	0.71
PhyloP100		0.61
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: rs9658757; hg19: chr10-90769455;