rs5030766

Variant names:

• chr10-88990843-A-G
• rs5030766
• ENST00000479522.6:n.-34A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000652046.1(FAS):​c.-34A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 1,614,070 control chromosomes in the GnomAD database, including 369 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (90 hom., cov: 33)
  • Exomes 𝑓: 0.016 (279 hom.)
• Consequence: FAS ENST00000652046.1 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.645
• Publications: 7 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:):

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 10-88990843-A-G is Benign according to our data. Variant chr10-88990843-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 301520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0619 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000652046.1. 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.-34A>G		5_prime_UTR	Exon 1 of 9	NP_000034.1
	FAS	NR_028033.4		n.46A>G		non_coding_transcript_exon	Exon 1 of 7
	FAS	NR_028034.4		n.46A>G		non_coding_transcript_exon	Exon 1 of 6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	ENST00000479522.6	TSL:1	n.-34A>G		non_coding_transcript_exon	Exon 1 of 6	ENSP00000424113.1
	FAS	ENST00000492756.7	TSL:1	n.-34A>G		non_coding_transcript_exon	Exon 1 of 7	ENSP00000422453.1
	FAS	ENST00000652046.1	MANE Select	c.-34A>G		5_prime_UTR	Exon 1 of 9	ENSP00000498466.1

Frequencies

GnomAD3 genomes AF: 0.0269 AC: 4096 AN: 152148 Hom.: 90 Cov.: 33

Gnomad AFR AF: 0.0641

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.0277

GnomAD2 exomes AF: 0.0148 AC: 3716 AN: 251272 AF XY: 0.0143

Gnomad AFR exome AF: 0.0636

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.0166

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.00328

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.0174

GnomAD4 exome AF: 0.0162 AC: 23706 AN: 1461804 Hom.: 279 Cov.: 31 AF XY: 0.0159 AC XY: 11565 AN XY: 727208

African (AFR) AF: 0.0693 AC: 2319 AN: 33480

American (AMR) AF: 0.0113 AC: 507 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 436 AN: 26136

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39700

South Asian (SAS) AF: 0.0140 AC: 1204 AN: 86254

European-Finnish (FIN) AF: 0.00395 AC: 211 AN: 53410

Middle Eastern (MID) AF: 0.0113 AC: 65 AN: 5768

European-Non Finnish (NFE) AF: 0.0161 AC: 17940 AN: 1111942

Other (OTH) AF: 0.0168 AC: 1014 AN: 60392

GnomAD4 genome AF: 0.0269 AC: 4099 AN: 152266 Hom.: 90 Cov.: 33 AF XY: 0.0255 AC XY: 1901 AN XY: 74456

African (AFR) AF: 0.0639 AC: 2656 AN: 41546

American (AMR) AF: 0.0182 AC: 279 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5166

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4824

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0140 AC: 952 AN: 68024

Other (OTH) AF: 0.0274 AC: 58 AN: 2116

Alfa AF: 0.0194 Hom.: 100

Bravo AF: 0.0308

Asia WGS AF: 0.0130 AC: 47 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autoimmune lymphoproliferative syndrome type 1 (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	Moyamoya disease (1)
-	-	1	Multisystemic smooth muscle dysfunction syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.8
DANN	Benign	0.55
PhyloP100		-0.65
PromoterAI		-0.17	Neutral
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5030766; hg19: chr10-90750600;