rs5030766

chr10-88990843-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.645

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]

(HGNC:):

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]

ACMG classification

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/exons	MANE	UniProt
FAS	NM_000043.6	c.-34A>G		5_prime_UTR_variant	1/9	ENST00000652046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAS	ENST00000652046.1	c.-34A>G		5_prime_UTR_variant	1/9		NM_000043.6	A2
	ENST00000651408.1	n.3407T>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0269 AC: 4096 AN: 152148 Hom.: 90 Cov.: 33

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.: 47 AF XY: 0.0143 AC XY: 1949 AN XY: 135854

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.: 31 AF XY: 0.0159 AC XY: 11565 AN XY: 727208

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.: 90 Cov.: 33 AF XY: 0.0255 AC XY: 1901 AN XY: 74456

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.: 17

Bravo AF: 0.0308

Asia WGS AF: 0.0130 AC: 47 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, flagged submission

clinical testing

GeneDx

Jul 31, 2015

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

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 31, 2015

- -

Autoimmune lymphoproliferative syndrome type 1 Benign:1

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	-0.79
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

Other links and lift over

dbSNP: rs5030766; hg19: chr10-90750600;