10-88990582-G-A

Position:

chr10-88990582-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000357339(FAS):c.-295G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00701 in 664,538 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0077 ( 43 hom. )

Consequence

FAS
ENST00000357339 5_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.29

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=-0.76).

BP6

Variant 10-88990582-G-A is Benign according to our data. Variant chr10-88990582-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 301517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00477 (726/152286) while in subpopulation SAS AF= 0.0195 (94/4822). AF 95% confidence interval is 0.0163. There are 6 homozygotes in gnomad4. There are 381 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Protein	UniProt
ACTA2	NM_001141945.3 linkuse as main transcript	c.-24+357C>T	intron_variant	NP_001135417.1	P62736D2JYH4
ACTA2	NM_001320855.2 linkuse as main transcript	c.-24+440C>T	intron_variant	NP_001307784.1	P62736D2JYH4
ACTA2	NM_001406462.1 linkuse as main transcript	c.-182+440C>T	intron_variant	NP_001393391.1

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	Protein	UniProt
FAS	ENST00000357339 linkuse as main transcript	c.-295G>A	5_prime_UTR_variant	1/8	1	ENSP00000349896.2	P25445-6
ACTA2	ENST00000415557.2 linkuse as main transcript	c.-24+357C>T	intron_variant		3	ENSP00000396730.2	F6QUT6
ACTA2	ENST00000458159.6 linkuse as main transcript	c.-24+440C>T	intron_variant		3	ENSP00000398239.2	F6UVQ4

Frequencies

GnomAD3 genomes

AF:

0.00479

AC:

729

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0197

Gnomad FIN

AF:

0.00368

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00642

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00725

AC:

958

AN:

132198

Hom.:

AF XY:

0.00891

AC XY:

641

AN XY:

71946

show subpopulations

Gnomad AFR exome

AF:

0.00112

Gnomad AMR exome

AF:

0.00332

Gnomad ASJ exome

AF:

0.00184

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0224

Gnomad FIN exome

AF:

0.00387

Gnomad NFE exome

AF:

0.00605

Gnomad OTH exome

AF:

0.00591

GnomAD4 exome

AF:

0.00768

AC:

3933

AN:

512252

Hom.:

Cov.:

AF XY:

0.00890

AC XY:

2474

AN XY:

278048

show subpopulations

Gnomad4 AFR exome

AF:

0.00139

Gnomad4 AMR exome

AF:

0.00383

Gnomad4 ASJ exome

AF:

0.00172

Gnomad4 EAS exome

AF:

0.0000341

Gnomad4 SAS exome

AF:

0.0222

Gnomad4 FIN exome

AF:

0.00548

Gnomad4 NFE exome

AF:

0.00694

Gnomad4 OTH exome

AF:

0.00626

GnomAD4 genome

AF:

0.00477

AC:

726

AN:

152286

Hom.:

Cov.:

AF XY:

0.00512

AC XY:

381

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.00536

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0195

Gnomad4 FIN

AF:

0.00368

Gnomad4 NFE

AF:

0.00642

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00613

Hom.:

Bravo

AF:

0.00459

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Moyamoya disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Multisystemic smooth muscle dysfunction syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Autoimmune lymphoproliferative syndrome type 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

8.5

DANN

Benign

0.89

Splicing

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