ENST00000313771.10:n.296A>G

Variant names:

• chr10-88991583-A-G
• rs3740286
• ENST00000313771.10:n.296A>G

Variant summary

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

The ENST00000313771.10(FAS):​n.296A>G variant causes a non coding transcript exon 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 ENST00000313771.10 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.12
• Publications: 29 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]

ENSG00000286116 (HGNC:):

FAS-AS1 (HGNC:37128): (FAS antisense RNA 1)

ACTA2 (HGNC:130): (actin alpha 2, smooth muscle) This gene encodes one of six different actin proteins. Actins are highly conserved proteins that are involved in cell motility, structure, integrity, and intercellular signaling. The encoded protein is a smooth muscle actin that is involved in vascular contractility and blood pressure homeostasis. Mutations in this gene cause a variety of vascular diseases, such as thoracic aortic disease, coronary artery disease, stroke, and Moyamoya disease, as well as multisystemic smooth muscle dysfunction syndrome. [provided by RefSeq, Sep 2017]

ACTA2 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• multisystemic smooth muscle dysfunction syndrome

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• aortic aneurysm, familial thoracic 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• Moyamoya disease 5

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
• connective tissue disorder

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000313771.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	NM_000043.6	MANE Select	c.30+677A>G		intron	N/A	NP_000034.1
	FAS-AS1	NR_028371.1		n.1393T>C		non_coding_transcript_exon	Exon 1 of 1
	FAS	NR_135314.2		n.153A>G		non_coding_transcript_exon	Exon 1 of 9

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	ENST00000313771.10	TSL:1	n.296A>G		non_coding_transcript_exon	Exon 1 of 9
	FAS	ENST00000652046.1	MANE Select	c.30+677A>G		intron	N/A	ENSP00000498466.1
	FAS	ENST00000357339.7	TSL:1	c.30+677A>G		intron	N/A	ENSP00000349896.2

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

African (AFR) AF: 0.300 AC: 3 AN: 10

American (AMR) AF: 0.301 AC: 103 AN: 342

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 7 AN: 24

East Asian (EAS) AF: 0.660 AC: 33 AN: 50

South Asian (SAS) AF: 0.447 AC: 134 AN: 300

European-Finnish (FIN) AF: 0.300 AC: 6 AN: 20

Middle Eastern (MID) AF: 0.500 AC: 3 AN: 6

European-Non Finnish (NFE) AF: 0.329 AC: 450 AN: 1368

Other (OTH) AF: 0.325 AC: 26 AN: 80

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

African (AFR) AF: 0.197 AC: 8164 AN: 41542

American (AMR) AF: 0.353 AC: 5401 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1502 AN: 3466

East Asian (EAS) AF: 0.521 AC: 2694 AN: 5172

South Asian (SAS) AF: 0.443 AC: 2127 AN: 4806

European-Finnish (FIN) AF: 0.381 AC: 4034 AN: 10592

Middle Eastern (MID) AF: 0.370 AC: 108 AN: 292

European-Non Finnish (NFE) AF: 0.367 AC: 24934 AN: 67986

Other (OTH) AF: 0.347 AC: 733 AN: 2110

Alfa AF: 0.339 Hom.: 5828

Bravo AF: 0.320

Asia WGS AF: 0.407 AC: 1414 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Benign	0.73
PhyloP100		1.1
PromoterAI		0.084	Neutral
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: rs3740286; hg19: chr10-90751340;