10-88990186-T-C

Variant names:

• chr10-88990186-T-C
• rs2234768
• ENST00000651408.1:n.4064A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000651408.1(ENSG00000286116):​n.4064A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0878 in 152,298 control chromosomes in the GnomAD database, including 765 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.088 (765 hom., cov: 32)
• Consequence: ENSG00000286116 ENST00000651408.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.282
• Publications: 13 publications found

Genes affected

ENSG00000286116 (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]

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 Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• autoimmune lymphoproliferative syndrome type 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTA2	NM_001141945.3	c.-24+753A>G		intron_variant	Intron 1 of 8		NP_001135417.1
ACTA2	NM_001320855.2	c.-24+836A>G		intron_variant	Intron 1 of 8		NP_001307784.1
ACTA2	NM_001406462.1	c.-182+836A>G		intron_variant	Intron 1 of 9		NP_001393391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000286116	ENST00000651408.1	n.4064A>G		non_coding_transcript_exon_variant	Exon 1 of 1
ACTA2	ENST00000415557.2	c.-24+753A>G		intron_variant	Intron 1 of 8	3		ENSP00000396730.2
ACTA2	ENST00000458159.6	c.-24+836A>G		intron_variant	Intron 1 of 8	3		ENSP00000398239.2

Frequencies

GnomAD3 genomes AF: 0.0880 AC: 13386 AN: 152182 Hom.: 767 Cov.: 32

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0828

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.00596

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.0926

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0878 AC: 13377 AN: 152298 Hom.: 765 Cov.: 32 AF XY: 0.0874 AC XY: 6508 AN XY: 74476

African (AFR) AF: 0.0230 AC: 957 AN: 41572

American (AMR) AF: 0.0827 AC: 1266 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 437 AN: 3470

East Asian (EAS) AF: 0.00617 AC: 32 AN: 5186

South Asian (SAS) AF: 0.110 AC: 533 AN: 4824

European-Finnish (FIN) AF: 0.144 AC: 1527 AN: 10612

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8316 AN: 68008

Other (OTH) AF: 0.0912 AC: 193 AN: 2116

Alfa AF: 0.0907 Hom.: 116

Bravo AF: 0.0805

Asia WGS AF: 0.0480 AC: 167 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.9
DANN	Benign	0.41
PhyloP100		-0.28
PromoterAI		0.059	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2234768; hg19: chr10-90749943;