rs4064

Positions:

• chr10-88991623-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000043.6(FAS):​c.30+717G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 153,676 control chromosomes in the GnomAD database, including 7,404 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 0.30 (7313 hom., cov: 33)
  • Exomes 𝑓: 0.36 (91 hom.)
• Consequence: FAS NM_000043.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.416

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAS	NM_000043.6	c.30+717G>C		intron_variant		ENST00000652046.1	NP_000034.1
FAS-AS1	NR_028371.1	n.1353C>G		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046.1	c.30+717G>C		intron_variant			NM_000043.6	ENSP00000498466	A2
	ENST00000651408.1	n.2627C>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45430 AN: 152010 Hom.: 7305 Cov.: 33

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.0216

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.288

GnomAD4 exome AF: 0.357 AC: 552 AN: 1548 Hom.: 91 Cov.: 0 AF XY: 0.343 AC XY: 293 AN XY: 854

Gnomad4 AFR exome AF: 0.333

Gnomad4 AMR exome AF: 0.388

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.261

Gnomad4 FIN exome AF: 0.429

Gnomad4 NFE exome AF: 0.377

Gnomad4 OTH exome AF: 0.300

GnomAD4 genome AF: 0.299 AC: 45463 AN: 152128 Hom.: 7313 Cov.: 33 AF XY: 0.297 AC XY: 22082 AN XY: 74380

Gnomad4 AFR AF: 0.236

Gnomad4 AMR AF: 0.314

Gnomad4 ASJ AF: 0.278

Gnomad4 EAS AF: 0.0215

Gnomad4 SAS AF: 0.202

Gnomad4 FIN AF: 0.342

Gnomad4 NFE AF: 0.356

Gnomad4 OTH AF: 0.291

Alfa AF: 0.332 Hom.: 1040

Bravo AF: 0.298

Asia WGS AF: 0.140 AC: 486 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.3
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs4064; hg19: chr10-90751380;