10-88957535-C-G

Variant names:

• chr10-88957535-C-G
• rs12258754
• ENST00000371927.7:c.1255-15647C>G

Variant summary

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

The ENST00000371927.7(STAMBPL1):​c.1255-15647C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 152,032 control chromosomes in the GnomAD database, including 10,957 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 0.34 (10957 hom., cov: 32)
• Consequence: STAMBPL1 ENST00000371927.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0500
• Publications: 5 publications found

Genes affected

STAMBPL1 (HGNC:24105): (STAM binding protein like 1) Predicted to enable Lys63-specific deubiquitinase activity and thiol-dependent deubiquitinase. Predicted to be involved in protein K63-linked deubiquitination. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000371927.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA2	NM_001141945.3		c.-23-8582G>C		intron	N/A	NP_001135417.1
	ACTA2	NM_001320855.2		c.-23-8582G>C		intron	N/A	NP_001307784.1
	ACTA2	NM_001406462.1		c.-23-8582G>C		intron	N/A	NP_001393391.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAMBPL1	ENST00000371927.7	TSL:2	c.1255-15647C>G		intron	N/A	ENSP00000360995.3
	ACTA2	ENST00000415557.2	TSL:3	c.-23-8582G>C		intron	N/A	ENSP00000396730.2
	ACTA2	ENST00000458159.6	TSL:3	c.-23-8582G>C		intron	N/A	ENSP00000398239.2

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52365 AN: 151914 Hom.: 10929 Cov.: 32

Gnomad AFR AF: 0.583

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.413

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.328

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

GnomAD4 genome AF: 0.345 AC: 52441 AN: 152032 Hom.: 10957 Cov.: 32 AF XY: 0.342 AC XY: 25412 AN XY: 74306

African (AFR) AF: 0.583 AC: 24162 AN: 41432

American (AMR) AF: 0.282 AC: 4302 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1119 AN: 3470

East Asian (EAS) AF: 0.413 AC: 2132 AN: 5156

South Asian (SAS) AF: 0.459 AC: 2212 AN: 4818

European-Finnish (FIN) AF: 0.134 AC: 1419 AN: 10606

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.239 AC: 16224 AN: 67958

Other (OTH) AF: 0.328 AC: 695 AN: 2116

Alfa AF: 0.125 Hom.: 193

Bravo AF: 0.362

Asia WGS AF: 0.449 AC: 1560 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.0
DANN	Benign	0.38
PhyloP100		-0.050
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: rs12258754; hg19: chr10-90717292;