rs2274355

Variant names:

• chr10-88990782-G-A
• rs2274355
• ENST00000357339.7:c.-95G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000357339.7(FAS):​c.-95G>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 0.00704 in 1,541,802 control chromosomes in the GnomAD database, including 568 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (319 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (249 hom.)
• Consequence: FAS ENST00000357339.7 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0530
• Publications: 3 publications found

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]

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), G2P, Orphanet
• 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
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000286116 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 10-88990782-G-A is Benign according to our data. Variant chr10-88990782-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 301519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000357339.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA2	NM_001141945.3		c.-24+157C>T		intron	N/A	NP_001135417.1	D2JYH4
	ACTA2	NM_001320855.2		c.-24+240C>T		intron	N/A	NP_001307784.1	P62736
	ACTA2	NM_001406462.1		c.-182+240C>T		intron	N/A	NP_001393391.1	P62736

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	ENST00000357339.7	TSL:1	c.-95G>A		5_prime_UTR	Exon 1 of 8	ENSP00000349896.2	P25445-6
	FAS	ENST00000479522.6	TSL:1	n.-95G>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000424113.1	P25445-3
	FAS	ENST00000492756.7	TSL:1	n.-95G>A		non_coding_transcript_exon	Exon 1 of 7	ENSP00000422453.1	P25445-5

Frequencies

GnomAD3 genomes AF: 0.0358 AC: 5455 AN: 152214 Hom.: 317 Cov.: 33

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00500

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0272

GnomAD2 exomes AF: 0.00990 AC: 2390 AN: 241412 AF XY: 0.00720

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.00632

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00614

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000222

Gnomad OTH exome AF: 0.00439

GnomAD4 exome AF: 0.00388 AC: 5393 AN: 1389470 Hom.: 249 Cov.: 23 AF XY: 0.00345 AC XY: 2397 AN XY: 695020

African (AFR) AF: 0.121 AC: 3866 AN: 31898

American (AMR) AF: 0.00730 AC: 322 AN: 44112

Ashkenazi Jewish (ASJ) AF: 0.0000390 AC: 1 AN: 25660

East Asian (EAS) AF: 0.00667 AC: 262 AN: 39264

South Asian (SAS) AF: 0.00279 AC: 236 AN: 84460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52414

Middle Eastern (MID) AF: 0.00339 AC: 19 AN: 5608

European-Non Finnish (NFE) AF: 0.000169 AC: 177 AN: 1048194

Other (OTH) AF: 0.00881 AC: 510 AN: 57860

GnomAD4 genome AF: 0.0359 AC: 5467 AN: 152332 Hom.: 319 Cov.: 33 AF XY: 0.0340 AC XY: 2536 AN XY: 74504

African (AFR) AF: 0.123 AC: 5121 AN: 41568

American (AMR) AF: 0.0146 AC: 224 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00501 AC: 26 AN: 5188

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68018

Other (OTH) AF: 0.0270 AC: 57 AN: 2114

Alfa AF: 0.0142 Hom.: 15

Bravo AF: 0.0405

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autoimmune lymphoproliferative syndrome type 1 (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	Moyamoya disease (1)
-	-	1	Multisystemic smooth muscle dysfunction syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.9
DANN	Benign	0.82
PhyloP100		-0.053
PromoterAI		-0.032	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2274355; hg19: chr10-90750539;