rs2234767

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 ENST00000690268.1(FAS):c.31G>A (p.Ala11Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. Note: ENST00000690268.1 is not a MANE Select or MANE Plus Clinical transcript for FAS; 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 0.134 (AC=72,620) in the gnomAD database across 543,676 control chromosomes, including 6,468 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.415. In-silico predictor (REVEL) classifies this variant as likely benign. Variant has been reported in ClinVar as Benign/Likely Benign (★).

Frequency

Genomes: 𝑓 0.11 ( 1426 hom., cov: 32)

Exomes 𝑓: 0.14 ( 5042 hom. )

Consequence

FAS
ENST00000690268.1 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1O:1

Conservation

PhyloP100: -0.866

Publications

216 publications found

Variant links:

COSMIC-nc: COSV58238613

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]

FAS Gene-Disease associations (from GenCC):

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

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):

multisystemic smooth muscle dysfunction syndrome
Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P
aortic aneurysm, familial thoracic 6
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Moyamoya disease 5
Inheritance: AD Classification: STRONG Submitted by: G2P, Genomics England PanelApp
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:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript ENST00000690268.1, 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 = 0.4151 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: ENST00000690268.1. 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+1440C>T	intron	N/A	NP_001135417.1	D2JYH4
ACTA2	NM_001320855.2	c.-24+1523C>T	intron	N/A	NP_001307784.1	P62736
ACTA2	NM_001406462.1	c.-182+1523C>T	intron	N/A	NP_001393391.1	P62736

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAS	ENST00000690268.1		c.31G>A	p.Ala11Thr	missense	Exon 3 of 11	ENSP00000509810.1	Q59FU8
ACTA2	ENST00000415557.2	TSL:3	c.-24+1440C>T		intron	N/A	ENSP00000396730.2	P62736
ACTA2	ENST00000458159.6	TSL:3	c.-24+1523C>T		intron	N/A	ENSP00000398239.2	P62736

Frequencies

GnomAD3 genomes

AF:

0.114

AC:

17311

AN:

151962

Hom.:

1428

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0470

Gnomad AMI

AF:

0.0658

Gnomad AMR

AF:

0.163

Gnomad ASJ

AF:

0.123

Gnomad EAS

AF:

0.420

Gnomad SAS

AF:

0.188

Gnomad FIN

AF:

0.121

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.113

Gnomad OTH

AF:

0.129

GnomAD2 exomes

AF:

0.151

AC:

34536

AN:

229260

AF XY:

0.149

show subpopulations

Gnomad AFR exome

AF:

0.0447

Gnomad AMR exome

AF:

0.172

Gnomad ASJ exome

AF:

0.114

Gnomad EAS exome

AF:

0.425

Gnomad FIN exome

AF:

0.120

Gnomad NFE exome

AF:

0.112

Gnomad OTH exome

AF:

0.139

GnomAD4 exome

AF:

0.141

AC:

55307

AN:

391596

Hom.:

5042

Cov.:

AF XY:

0.142

AC XY:

31435

AN XY:

221656

show subpopulations

African (AFR)

AF:

0.0480

AC:

542

AN:

11292

American (AMR)

AF:

0.171

AC:

6301

AN:

36810

Ashkenazi Jewish (ASJ)

AF:

0.118

AC:

1581

AN:

13396

East Asian (EAS)

AF:

0.423

AC:

7761

AN:

18348

South Asian (SAS)

AF:

0.171

AC:

11427

AN:

66950

European-Finnish (FIN)

AF:

0.116

AC:

1968

AN:

16922

Middle Eastern (MID)

AF:

0.111

AC:

336

AN:

3014

European-Non Finnish (NFE)

AF:

0.111

AC:

22877

AN:

206248

Other (OTH)

AF:

0.135

AC:

2514

AN:

18616

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

2610

5220

7830

10440

13050

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

376

752

1128

1504

1880

<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:

0.114

AC:

17313

AN:

152080

Hom.:

1426

Cov.:

AF XY:

0.118

AC XY:

8766

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.0470

AC:

1948

AN:

41480

American (AMR)

AF:

0.163

AC:

2500

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.123

AC:

426

AN:

3468

East Asian (EAS)

AF:

0.420

AC:

2171

AN:

5166

South Asian (SAS)

AF:

0.187

AC:

902

AN:

4816

European-Finnish (FIN)

AF:

0.121

AC:

1280

AN:

10590

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.113

AC:

7703

AN:

67944

Other (OTH)

AF:

0.130

AC:

275

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

721

1443

2164

2886

3607

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

190

380

570

760

950

<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:

0.117

Hom.:

2462

Bravo

AF:

0.112

Asia WGS

AF:

0.327

AC:

1135

AN:

3478

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.422

AC:

51823

AN:

122694

Turkish Variome

AF:

0.118

AC:

183

AN:

1546

Hom.:

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.409

AC:

3667

AN:

8960

Hom.:

749

ABraOM SABE-WGS-1171

AF:

0.119

AC:

279

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

LUNG CANCER, SUSCEPTIBILITY TO (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.31

(source)

DANN

Benign

0.50

PhyloP100

-0.87

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

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over