rs1800682

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is The variant received -14 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_Moderate

The NM_001141945.3(ACTA2):c.-24+733T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. Note: NM_001141945.3 is not a MANE Select or MANE Plus Clinical transcript for ACTA2; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.536 (AC=81,523) in the gnomAD database across 152,064 control chromosomes, including 22,963 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.714. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Variant has been reported in ClinVar as Benign/Likely Benign (★).

Frequency

Genomes: 𝑓 0.54 ( 22963 hom., cov: 32)

Consequence

ACTA2
NM_001141945.3 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0250

Publications

352 publications found

Variant links:

Genes affected

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):

multisystemic smooth muscle dysfunction syndrome
Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet
aortic aneurysm, familial thoracic 6
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
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
familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACTA2 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 Gene-Disease associations (from GenCC):

autoimmune lymphoproliferative syndrome
Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, PanelApp Australia
autoimmune lymphoproliferative syndrome type 1
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
FAS-related autoimmune lymphoproliferative immune disorder
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen

FAS links:

ENSG00000286116 (HGNC:):

ENSG00000286116 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001141945.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -14 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); No splicing predictor data available.; Germline computational verdict: benign (Strong).

BP6

ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.7143 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001141945.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
ACTA2	NM_001141945.3	c.-24+733T>C	intron	N/A	NP_001135417.1	D2JYH4
ACTA2	NM_001320855.2	c.-24+816T>C	intron	N/A	NP_001307784.1	P62736
ACTA2	NM_001406462.1	c.-182+816T>C	intron	N/A	NP_001393391.1	P62736

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ACTA2	ENST00000415557.2	TSL:3	c.-24+733T>C	intron	N/A	ENSP00000396730.2	P62736
ACTA2	ENST00000458159.6	TSL:3	c.-24+816T>C	intron	N/A	ENSP00000398239.2	P62736
ACTA2	ENST00000713602.1		c.-182+816T>C	intron	N/A	ENSP00000518898.1	P62736

Frequencies

GnomAD3 genomes

AF:

0.536

AC:

81399

AN:

151942

Hom.:

22905

Cov.:

show subpopulations

Gnomad AFR

AF:

0.721

Gnomad AMI

AF:

0.479

Gnomad AMR

AF:

0.530

Gnomad ASJ

AF:

0.411

Gnomad EAS

AF:

0.472

Gnomad SAS

AF:

0.435

Gnomad FIN

AF:

0.450

Gnomad MID

AF:

0.481

Gnomad NFE

AF:

0.458

Gnomad OTH

AF:

0.513

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

GnomAD4 genome

AF:

0.536

AC:

81523

AN:

152064

Hom.:

22963

Cov.:

AF XY:

0.535

AC XY:

39759

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.721

AC:

29904

AN:

41470

American (AMR)

AF:

0.531

AC:

8119

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.411

AC:

1425

AN:

3468

East Asian (EAS)

AF:

0.472

AC:

2439

AN:

5166

South Asian (SAS)

AF:

0.434

AC:

2092

AN:

4820

European-Finnish (FIN)

AF:

0.450

AC:

4761

AN:

10580

Middle Eastern (MID)

AF:

0.490

AC:

142

AN:

290

European-Non Finnish (NFE)

AF:

0.458

AC:

31118

AN:

67964

Other (OTH)

AF:

0.516

AC:

1087

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1847

3693

5540

7386

9233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

686

1372

2058

2744

3430

<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:

0.487

Hom.:

78067

Bravo

AF:

0.550

Asia WGS

AF:

0.533

AC:

1854

AN:

3478

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.514

AC:

63111

AN:

122762

Turkish Variome

AF:

0.417

AC:

645

AN:

1546

Hom.:

139

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.452

AC:

4049

AN:

8960

Hom.:

906

ABraOM SABE-WGS-1171

AF:

0.544

AC:

1275

AN:

2342

Hom.:

359

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autoimmune lymphoproliferative syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

5.1

(source)

DANN

Benign

0.54

PhyloP100

-0.025

PromoterAI

0.062

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over