rs6586160

Positions:

• chr10-88980795-G-A
• chr10-88980795-G-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
FAS	XM_011539764.3	c.-2137G>A		5_prime_UTR_variant	1/10		XP_011538066.1
ACTA2	NM_001141945.3	c.-24+10144C>T		intron_variant			NP_001135417.1
ACTA2	NM_001320855.2	c.-24+10227C>T		intron_variant			NP_001307784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000415557.2	c.-24+10144C>T		intron_variant		3		ENSP00000396730	P1
ACTA2	ENST00000458159.6	c.-24+10227C>T		intron_variant		3		ENSP00000398239	P1
FAS	ENST00000688239.1	n.260+7448G>A		intron_variant, non_coding_transcript_variant
FAS	ENST00000696723.1	n.3552+7448G>A		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR AF: 0.880

Gnomad4 AMR AF: 0.725

Gnomad4 ASJ AF: 0.753

Gnomad4 EAS AF: 0.546

Gnomad4 SAS AF: 0.673

Gnomad4 FIN AF: 0.729

Gnomad4 NFE AF: 0.739

Gnomad4 OTH AF: 0.754

Alfa AF: 0.781 Hom.: 6896

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs6586160; hg19: chr10-90740552;