rs5030765

Variant names:

• chr10-88990479-C-T
• rs5030765
• ENST00000651408.1:n.3771G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000651408.1(ENSG00000286116):​n.3771G>A 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 0.00032 in 549,784 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: ENSG00000286116 ENST00000651408.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.27
• Publications: 3 publications found

Genes affected

ENSG00000286116 (HGNC:):

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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTA2	NM_001141945.3	c.-24+460G>A		intron_variant	Intron 1 of 8		NP_001135417.1
ACTA2	NM_001320855.2	c.-24+543G>A		intron_variant	Intron 1 of 8		NP_001307784.1
ACTA2	NM_001406462.1	c.-182+543G>A		intron_variant	Intron 1 of 9		NP_001393391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000286116	ENST00000651408.1	n.3771G>A		non_coding_transcript_exon_variant	Exon 1 of 1
FAS	ENST00000688239.1	n.645C>T		non_coding_transcript_exon_variant	Exon 4 of 4
ACTA2	ENST00000415557.2	c.-24+460G>A		intron_variant	Intron 1 of 8	3		ENSP00000396730.2

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000314 AC: 125 AN: 397568 Hom.: 0 AF XY: 0.000306 AC XY: 66 AN XY: 215468

African (AFR) AF: 0.000152 AC: 2 AN: 13142

American (AMR) AF: 0.0000336 AC: 1 AN: 29744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15314

East Asian (EAS) AF: 0.00 AC: 0 AN: 21830

South Asian (SAS) AF: 0.00 AC: 0 AN: 57832

European-Finnish (FIN) AF: 0.0000649 AC: 1 AN: 15410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1750

European-Non Finnish (NFE) AF: 0.000540 AC: 119 AN: 220536

Other (OTH) AF: 0.0000909 AC: 2 AN: 22010

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74366

African (AFR) AF: 0.000169 AC: 7 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000617 AC: 42 AN: 68048

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000485 Hom.: 0

Bravo AF: 0.000366

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Benign	0.92
PhyloP100		1.3
PromoterAI		0.067	Neutral

Splicing

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

Other links and lift over

dbSNP: rs5030765; hg19: chr10-90750236;