chr10-88980795-G-A

Variant names:

• chr10-88980795-G-A
• rs6586160
• XM_011539764.3:c.-2137G>A

Variant summary

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

The XM_011539764.3(FAS):​c.-2137G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.768 in 152,122 control chromosomes in the GnomAD database, including 45,454 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 0.77 (45454 hom., cov: 32)
• Consequence: FAS XM_011539764.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.141
• Publications: 3 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]

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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.873 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAS	XM_011539764.3	c.-2137G>A		5_prime_UTR_variant	Exon 1 of 10		XP_011538066.1
ACTA2	NM_001141945.3	c.-24+10144C>T		intron_variant	Intron 1 of 8		NP_001135417.1
ACTA2	NM_001320855.2	c.-24+10227C>T		intron_variant	Intron 1 of 8		NP_001307784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000415557.2	c.-24+10144C>T		intron_variant	Intron 1 of 8	3		ENSP00000396730.2
ACTA2	ENST00000458159.6	c.-24+10227C>T		intron_variant	Intron 1 of 8	3		ENSP00000398239.2
ACTA2	ENST00000713602.1	c.-24+4002C>T		intron_variant	Intron 2 of 9			ENSP00000518898.1

Frequencies

GnomAD3 genomes AF: 0.768 AC: 116762 AN: 152004 Hom.: 45403 Cov.: 32

Gnomad AFR AF: 0.881

Gnomad AMI AF: 0.878

Gnomad AMR AF: 0.725

Gnomad ASJ AF: 0.753

Gnomad EAS AF: 0.547

Gnomad SAS AF: 0.672

Gnomad FIN AF: 0.729

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.739

Gnomad OTH AF: 0.753

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

GnomAD4 genome AF: 0.768 AC: 116876 AN: 152122 Hom.: 45454 Cov.: 32 AF XY: 0.766 AC XY: 56935 AN XY: 74352

African (AFR) AF: 0.880 AC: 36563 AN: 41528

American (AMR) AF: 0.725 AC: 11078 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.753 AC: 2613 AN: 3468

East Asian (EAS) AF: 0.546 AC: 2821 AN: 5162

South Asian (SAS) AF: 0.673 AC: 3241 AN: 4816

European-Finnish (FIN) AF: 0.729 AC: 7693 AN: 10556

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.739 AC: 50270 AN: 67990

Other (OTH) AF: 0.754 AC: 1592 AN: 2112

Alfa AF: 0.801 Hom.: 19575

Bravo AF: 0.776

Asia WGS AF: 0.594 AC: 2065 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.1
DANN	Benign	0.60
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs6586160; hg19: chr10-90740552;