rs9658676

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000651408.1(ENSG00000286116):n.3809G>T 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 0.01 in 494,206 control chromosomes in the GnomAD database, including 195 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 0.024 ( 159 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 36 hom. )

Consequence

ENSG00000286116
ENST00000651408.1 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.317

Publications

7 publications found

Variant links:

Genes affected

ENSG00000286116 (HGNC:):

ENSG00000286116 links:

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]

FAS links:

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

ACTA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0815 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
ACTA2	NM_001141945.3 link	c.-24+498G>T	intron_variant	Intron 1 of 8	NP_001135417.1	P62736D2JYH4
ACTA2	NM_001320855.2 link	c.-24+581G>T	intron_variant	Intron 1 of 8	NP_001307784.1	P62736D2JYH4
ACTA2	NM_001406462.1 link	c.-182+581G>T	intron_variant	Intron 1 of 9	NP_001393391.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
ENSG00000286116	ENST00000651408.1 link	n.3809G>T	non_coding_transcript_exon_variant	Exon 1 of 1
FAS	ENST00000688239.1 link	n.607C>A	non_coding_transcript_exon_variant	Exon 4 of 4
ACTA2	ENST00000415557.2 link	c.-24+498G>T	intron_variant	Intron 1 of 8	3	ENSP00000396730.2	F6QUT6

Frequencies

GnomAD3 genomes

AF:

0.0243

AC:

3702

AN:

152200

Hom.:

157

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0839

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0101

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.0229

GnomAD4 exome

AF:

0.00362

AC:

1236

AN:

341888

Hom.:

AF XY:

0.00291

AC XY:

532

AN XY:

182948

show subpopulations

African (AFR)

AF:

0.0823

AC:

954

AN:

11592

American (AMR)

AF:

0.00373

AC:

AN:

26254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12104

East Asian (EAS)

AF:

0.00

AC:

AN:

20060

South Asian (SAS)

AF:

0.000234

AC:

AN:

51390

European-Finnish (FIN)

AF:

0.00

AC:

AN:

11524

Middle Eastern (MID)

AF:

0.00279

AC:

AN:

1434

European-Non Finnish (NFE)

AF:

0.000218

AC:

AN:

188470

Other (OTH)

AF:

0.00666

AC:

127

AN:

19060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

117

175

234

292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0243

AC:

3708

AN:

152318

Hom.:

159

Cov.:

AF XY:

0.0230

AC XY:

1713

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0838

AC:

3482

AN:

41552

American (AMR)

AF:

0.0101

AC:

155

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68034

Other (OTH)

AF:

0.0227

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

175

349

524

698

873

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0304

Hom.:

Bravo

AF:

0.0277

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

6.6

(source)

DANN

Benign

0.53

PhyloP100

0.32

PromoterAI

0.00080

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over