chr10-88990582-G-A

Variant names:

• chr10-88990582-G-A
• rs9658677
• ENST00000357339.7:c.-295G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000357339.7(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 ENST00000357339.7 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.29
• Publications: 5 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, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• 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

ENSG00000286116 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

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+357C>T		intron	N/A	NP_001135417.1	D2JYH4
	ACTA2	NM_001320855.2		c.-24+440C>T		intron	N/A	NP_001307784.1	P62736
	ACTA2	NM_001406462.1		c.-182+440C>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.-295G>A		5_prime_UTR	Exon 1 of 8	ENSP00000349896.2	P25445-6
	ACTA2	ENST00000415557.2	TSL:3	c.-24+357C>T		intron	N/A	ENSP00000396730.2	P62736
	ACTA2	ENST00000458159.6	TSL:3	c.-24+440C>T		intron	N/A	ENSP00000398239.2	P62736

Frequencies

GnomAD3 genomes AF: 0.00479 AC: 729 AN: 152168 Hom.: 6 Cov.: 33

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

GnomAD2 exomes AF: 0.00725 AC: 958 AN: 132198 AF XY: 0.00891

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 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.: 43 Cov.: 0 AF XY: 0.00890 AC XY: 2474 AN XY: 278048

African (AFR) AF: 0.00139 AC: 21 AN: 15116

American (AMR) AF: 0.00383 AC: 128 AN: 33464

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 33 AN: 19164

East Asian (EAS) AF: 0.0000341 AC: 1 AN: 29304

South Asian (SAS) AF: 0.0222 AC: 1363 AN: 61518

European-Finnish (FIN) AF: 0.00548 AC: 159 AN: 29006

Middle Eastern (MID) AF: 0.00436 AC: 10 AN: 2294

European-Non Finnish (NFE) AF: 0.00694 AC: 2041 AN: 294132

Other (OTH) AF: 0.00626 AC: 177 AN: 28254

GnomAD4 genome AF: 0.00477 AC: 726 AN: 152286 Hom.: 6 Cov.: 33 AF XY: 0.00512 AC XY: 381 AN XY: 74470

African (AFR) AF: 0.00113 AC: 47 AN: 41560

American (AMR) AF: 0.00536 AC: 82 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0195 AC: 94 AN: 4822

European-Finnish (FIN) AF: 0.00368 AC: 39 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00642 AC: 437 AN: 68032

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00613 Hom.: 0

Bravo AF: 0.00459

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	8.5
DANN	Benign	0.89
PhyloP100		-2.3
PromoterAI		-0.16	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs9658677; hg19: chr10-90750339;