rs5030766

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000043.6(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
NM_000043.6 5_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.645

Variant links:

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 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 links:

ENSG00000286116 (HGNC:):

ENSG00000286116 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 301520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-88990843-A-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAS	NM_000043.6 link	c.-34A>G		5_prime_UTR_variant	Exon 1 of 9	ENST00000652046.1	NP_000034.1	P25445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046 link	c.-34A>G		5_prime_UTR_variant	Exon 1 of 9		NM_000043.6	ENSP00000498466.1		P25445-1

Frequencies

GnomAD3 genomes

AF:

0.0269

AC:

4096

AN:

152148

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0148

AC:

3716

AN:

251272

Hom.:

AF XY:

0.0143

AC XY:

1949

AN XY:

135854

show subpopulations

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 SAS exome

AF:

0.0143

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.:

AF XY:

0.0159

AC XY:

11565

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.0693

Gnomad4 AMR exome

AF:

0.0113

Gnomad4 ASJ exome

AF:

0.0167

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.0140

Gnomad4 FIN exome

AF:

0.00395

Gnomad4 NFE exome

AF:

0.0161

Gnomad4 OTH exome

AF:

0.0168

GnomAD4 genome

AF:

0.0269

AC:

4099

AN:

152266

Hom.:

Cov.:

AF XY:

0.0255

AC XY:

1901

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0639

Gnomad4 AMR

AF:

0.0182

Gnomad4 ASJ

AF:

0.0135

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.0133

Gnomad4 FIN

AF:

0.00358

Gnomad4 NFE

AF:

0.0140

Gnomad4 OTH

AF:

0.0274

Alfa

AF:

0.0194

Hom.:

Bravo

AF:

0.0308

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 31, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Jul 31, 2015

GeneDx

Significance: Benign

Review Status: flagged submission

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Moyamoya disease

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multisystemic smooth muscle dysfunction syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autoimmune lymphoproliferative syndrome type 1

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

2.8

DANN

Benign

0.55

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over