10-88991583-A-G

Position:

• chr10-88991583-A-G

Variant summary

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

The NM_000043.6(FAS):​c.30+677A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 154,376 control chromosomes in the GnomAD database, including 9,032 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 0.33 (8885 hom., cov: 33)
  • Exomes 𝑓: 0.35 (147 hom.)
• Consequence: FAS NM_000043.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.12

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAS	NM_000043.6	c.30+677A>G		intron_variant		ENST00000652046.1	NP_000034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046.1	c.30+677A>G		intron_variant			NM_000043.6	ENSP00000498466.1

Frequencies

GnomAD3 genomes AF: 0.329 AC: 50075 AN: 152056 Hom.: 8885 Cov.: 33

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.521

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.381

Gnomad MID AF: 0.376

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.349

GnomAD4 exome AF: 0.348 AC: 765 AN: 2200 Hom.: 147 Cov.: 0 AF XY: 0.366 AC XY: 427 AN XY: 1168

Gnomad4 AFR exome AF: 0.300

Gnomad4 AMR exome AF: 0.301

Gnomad4 ASJ exome AF: 0.292

Gnomad4 EAS exome AF: 0.660

Gnomad4 SAS exome AF: 0.447

Gnomad4 FIN exome AF: 0.300

Gnomad4 NFE exome AF: 0.329

Gnomad4 OTH exome AF: 0.325

GnomAD4 genome AF: 0.329 AC: 50079 AN: 152176 Hom.: 8885 Cov.: 33 AF XY: 0.334 AC XY: 24845 AN XY: 74386

Gnomad4 AFR AF: 0.197

Gnomad4 AMR AF: 0.353

Gnomad4 ASJ AF: 0.433

Gnomad4 EAS AF: 0.521

Gnomad4 SAS AF: 0.443

Gnomad4 FIN AF: 0.381

Gnomad4 NFE AF: 0.367

Gnomad4 OTH AF: 0.347

Alfa AF: 0.361 Hom.: 4895

Bravo AF: 0.320

Asia WGS AF: 0.407 AC: 1414 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs3740286; hg19: chr10-90751340;